Carbonylamino-benzimidazole derivatives as androgen receptor modulators

ABSTRACT

Compounds of structural formula (I) are modulators of the androgen receptor (AR) in a tissue selective manner. They are useful as agonists of the androgen receptor in bone and/or muscle tissue while antagonizing the AR in the prostate of a male patient or in the uterus of a female patient. These compounds are therefore useful in the enhancement of weakened muscle tone and the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, arthritic condition and joint repair, HIV-wasting, prostate cancer, cancer cachexia, Alzheimer s disease, muscular dystrophies, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US03/34345, filed Oct. 28, 2003, whichclaims priority under 35 U.S.C. § 119(e) from U.S. ProvisionalApplication Ser. No. 60/422,914, filed Nov. 01, 2002.

FIELD OF THE INVENTION

The present invention relates to carbonylamino-benzimidazolederivatives, their synthesis, and their use as androgen receptormodulators. More particularly, the compounds of the present inventionare tissue-selective androgen receptor modulators and are thereby usefulfor the treatment of conditions caused by androgen deficiency or whichcan be ameliorated by androgen administration, such as osteoporosis,periodontal disease, bone fracture, frailty, and sarcopenia.Additionally, the androgen receptor modulators of the present inventioncan be used to enhance muscle tone.

BACKGROUND OF THE INVENTION

The androgen receptor (AR) belongs to the superfamily of steroid/thyroidhormone nuclear receptors, whose other members include the estrogenreceptor (ER), the progesterone receptor (PR), the glucocorticoidreceptor (GR), and the mineralocorticoid receptor (MR). The AR isexpressed in numerous tissues of the body and is the receptor throughwhich the physiological as well as the pathophysiological effects ofendogenous androgen ligands, such as testosterone (M) anddihydrotestosterone (DHT), are expressed. Structurally, the AR iscomposed of three main functional domains: the ligand binding domain(LBD), the DNA-binding domain, and amino-terminal domain. A compoundthat binds to the AR and mimics the effects of an endogenous AR ligandis referred to as an AR agonist, whereas a compound that inhibits theeffects of an endogenous AR ligand is termed an AR antagonist.

Androgen ligand binding to the AR affords a ligand/receptor complex,which, subsequent to translocation inside the nucleus of the cell, bindsto specific regulatory DNA sequences (referred to as androgen responseelements or AREs) within the promoter or enhancer regions of the targetgene or genes present in the cell's nucleus. Other proteins termedcofactors are next recruited which bind to the amino-terminal domain orthe LBD of the receptor leading to gene transcription and subsequenttranslation to produce the protein(s) encoded by that gene or genes.

Androgen therapy has been used in the clinic to treat a variety of maledisorders, such as reproductive disorders and primary or secondary malehypogonadism. Moreover, a number of natural or synthetic AR agonistshave been clinically investigated for the treatment of musculoskeletaldisorders, such as bone disease, hematopoietic disorders, neuromusculardisease, rheumatological disease, wasting disease, and for hormonereplacement therapy (HRT), such as female androgen deficiency. Inaddition, AR antagonists, such as flutamide and bicalutamide, have beenused to treat prostate cancer. It would therefore be useful to haveavailable compounds that can activate (“agonize”) the function of the ARin a tissue-selective manner which would afford the desired beneficialosteo- and myoanabolic effects of androgens but without the negativeandrogenic properties, such as virilization and induction of anatherogenic lipid profile which can lead to cardiovascular disease.

The role of androgens in bone formation has been documented. Forexample, anabolic steroids, such as nandrolone decanoate or stanozolol,have been shown to increase bone mass in postmenopausal women. Thebeneficial effects of androgens on bone in postmenopausal osteoporosiswere documented in recent studies using combined testosterone andestrogen administration [Hofbauer, et al., “Androgen effects on bonemetabolism: recent progress and controversies,” Eur. J. Edocrinol. 140:271-286 (1999)]. Combined treatment significantly increased the rate andextent of the rise in bone mineral density (BMD) in the lumbar and hipregions, relative to treatment with estrogen alone. Additionally,estrogen-progestin combinations that incorporated an androgenicprogestin (such as norethindrone), rather than medroxyprogesteroneacetate, yielded greater improvements in hip BMD. These results haverecently been confirmed in a larger 2-year, double-blind comparisonstudy in which oral conjugated estrogen (CEE) and methyltestosteronecombinations were demonstrated to be effective in promoting accrual ofbone mass in the spine and hip, while conjugated estrogen therapy aloneprevented bone loss [“A two-year, double-blind comparison ofestrogen-androgen and conjugated estrogens in surgically menopausalwomen: Effects on bone mineral density, symptoms and lipid profiles,” J.Reprod. Med., 44: 1012-1020 (1999)]. Despite the beneficial effects ofandrogens in postmenopausal women, the use of androgens has been limitedbecause of the undesirable virilizing and metabolic action of androgens.The data from Watts and colleagues demonstrate that hot flushes decreasein women treated with CEE and methyltestosterone; however, 30% of thesewomen suffered from significant increases in acne 30 and facial hair, acomplication of all current androgen pharmacotherapies [Watts, et al.,“Comparison of oral estrogens and estrogens plus androgen on bonemineral density, menopausal symptoms, and lipid-lipoprotein profiles insurgical menopause,” Obstet. Gynecol., 85: 529-537 (1995)]. Moreover,the addition of methyltestosterone to CEE markedly decreased HDL levels,as seen in other studies. Therefore, non-tissue selective AR agonistscan increase the risk of cardiovascular disease. Thus, the virilizingpotential and negative effects on lipid profile of current androgentherapies provide a strong rationale for developing tissue-selectiveandrogen receptor agonists for bone. Reference is made to J. A. Kanis,“Other agents for generalized osteoporosis,” in Osteoporosis BlackwellScience, Ch. 8, pp. 196-227 (1994) for a discussion of non-selectiveanabolic steroids in the treatment of osteoporosis.

It is also well established that androgens play an important role inbone metabolism in men, which parallels the role of estrogens in women[Anderson, et al., “Androgen supplementation in eugonadal men withosteoporosis—effects of six months of treatment on bone mineral densityand cardiovascular risk factors,” Bone, 18: 171-177 (1996)]. Even ineugonadal men with established osteoporosis, the therapeutic response totestosterone treatment provided additional evidence that androgens exertimportant osteoanabolic effects. Mean lumbar BMD increased from 0.799gm/cm2 to 0.839 g/cm2, in 5 to 6 months in response to 250 mg oftestosterone ester administered intramuscularly every fortnight. Acommon scenario for androgen deficiency occurs in men with stage Dprostate cancer (metastatic) who undergo androgen deprivation therapy(ADT). Endocrine orchiectomy is achieved by long acting GnRH agonists,while androgen receptor blockade is implemented with flutamide,nilutamide, bicalutamide, or RU 58841 (AR antagonists). In response tohormonal deprivation, these men suffered from hot flushes, significantbone loss, weakness, and fatigue. In a recent pilot study of men withstage D prostate cancer, osteopenia (50% vs. 38%) and osteoporosis (38%vs. 25%) were more common in men who had undergone ADT for greater thanone year than the patients who did not undergo ADT [Wei, et al.,“Androgen deprivation therapy for prostate cancer results in significantloss of bone density,” Urology, 54: 607-611 (1999)]. Lumbar spine BMDwas significantly lower in men who had undergone ADT. Thus, in additionto the use of tissue selective AR agonists for osteoporosis, tissueselective AR antagonists in the prostate that lack antagonistic actionin bone and muscle can be useful agents for the treatment of prostatecancer, either alone or as an adjunct to traditional ADT such as with aGnRH agonist/antagonist [See also A. Stoch, et al., J. Clin. Endocrin.Metab., 86: 2787-2791 (2001)]. Tissue-selective AR antagonists can alsohave utility in the treatment of polycystic ovarian syndrome inpostmenopausal women [see C. A. Eagleson, et al., “Polycystic ovariansyndrome: evidence that flutamide restores sensitivity of thegonadotropin-releasing hormone pulse generator to inhibition byestradiol and progesterone,” J. Clin. Endocrinol. Metab., 85: 4047-4052(2000) and E. Diamanti-Kandarakis, “The Effect of a Pure AntiandrogenReceptor Blocker, Flutamide, on the Lipid Profile in the PolycysticOvary Syndrome,” Int. J. Endocrinol. Metab., 83: 2699-2705 (1998).

There is a need for more effective agents to treat osteopenia andosteoporosis in both men and women. Osteoporosis is characterized bybone loss, resulting from an imbalance between bone resorption(destruction) and bone formation, which starts in the fourth decade andcontinues throughout life at the rate of about 1-4% per year [Eastell,“Treatment of postmenopausal osteoporosis,” New Engl. J. Med., 338: 736(1998)]. In the United States, there are currently about 20 millionpeople with detectable fractures of the vertebrae due to osteoporosis.In addition, there are about 250,000 hip fractures per year due toosteoporosis, associated with a 12%-20% mortality rate within the firsttwo years, while 30% of patients require nursing home care after thefracture and many never become fully ambulatory again. In postmenopausalwomen, estrogen deficiency leads to increased bone resorption resultingin bone loss in the vertebrae of around 5% per year, immediatelyfollowing menopause. Thus, first line treatment/prevention of thiscondition is inhibition of bone resorption by bisphosphonates,estrogens, selective estrogen receptor modulators (SERMs), andcalcitonin. However, inhibitors of bone resorption are not sufficient torestore bone mass for patients who have already lost a significantamount of bone. The increase in spinal BMD attained by bisphosphonatetreatment can reach 11 after 7 years of treatment with alendronate. Inaddition, as the rate of bone turnover differs from site to site, higherin the trabecular bone of the vertebrae than in the cortex of the longbones, the bone resorption inhibitors are less effective in increasinghip BMD and preventing hip fracture. Therefore, osteoanabolic agents,which increase cortical bone formation and bone mass of long bones bystimulating periosteal bone formation, would address an unmet need inthe treatment of osteoporosis especially for patients with high risk ofhip fractures. The osteoanabolic agents also complement the boneresorption inhibitors that target the trabecular envelope, leading to abiomechanically favorable bone structure (Schmidt, et al., “Anabolicsteroid: Steroid effects on bone in women,” In: J. P. Bilezikian, etal., Ed., Principles of Bone Biology, San Diego: Academic Press, 1996).Tissue-selective AR agonists with diminished deleterious effects on thecardiovascular system and limited virilizing potential can be useful asa monotherapy for the prevention and/or treatment of femaleosteoporosis. In addition, a compound with osteoanabolic properties inbone and muscle but with reduced activity in the prostate and sexaccessory tissues can be useful for the prevention and/or treatment ofmale osteoporosis and osteopenia in men, particularly elderly men.

Selective androgen receptor modulators can also be useful to treatcertain hematopoietic disorders. It is known that androgens stimulaterenal hypertrophy and erythropoietin (EPO) production. Prior to theintroduction of recombinant human EPO, androgens were employed to treatanemia caused by chronic renal failure. In addition, androgens atpharmacological doses were found to increase serum EPO levels in anemicpatients with non-severe aplastic anemia and myelodysplastic syndromesbut not in non-anemic patients. Treatment modalities for anemia willrequire selective action such as can be provided by selective androgenreceptor modulators.

Furthermore, selective androgen receptor modulators can also haveclinical value as an adjunct to the treatment of obesity. This approachto lowering body fat is supported by published observations thatandrogen administration reduced subcutaneous and visceral abdominal fatin obese men [J. C. Lovejoy, et al., “Oral anabolic steroid treatment,but not parenteral androgen treatment, decreases abdominal fat in obese,older men,” Int. J. Obesity, 19: 614-624 (1995)]. Therefore, SARMsdevoid of androgenic effects on prostate can be beneficial in thetreatment of obese men. In a separate study, androgen administrationresulted in loss of subcutaneous abdominal fat in obese postmenopausalwomen [J. C. Lovejoy, et al., “Exogenous Androgens Influence BodyComposition and Regional Body Fat Distribution in Obese PostmenopausalWomen—A Clinical Research Center Study,” J. Clin. Endocrinol. Metab.,81: 2198-2203 (1996)]. In the later study, nandrolone decanoate, a weakandrogen and anabolic agent, was found to increase lean body mass andresting metabolic rate in obese postmenopausal women consuming aweight-reducing diet.

That androgen receptor agonists can also have therapeutic value againstneurodegenerative diseases such as Alzheimer's disease (AD) has alsobeen suggested. The ability of androgens to induce neuroprotectionthrough the androgen receptor was reported by J. Hammond, et al.,“Testosterone-mediated neuroprotection through the androgen receptor inhuman primary neurons,” J. Neurochem., 77: 1319-1326 (2001). Gouras etal. have observed that testosterone can reduce neuronal secretion ofAlzheimer's β-amyloid peptides and can therefore be protective in thetreatment of AD [(Proc. Nat. Acad. Sci., 97: 1202-1205 (2000)]. Amechanism via inhibition of hyperphosphorylation of proteins implicatedin the progression AD has also been described [S. Papasozomenos,“Testosterone prevents the heat shock-induced overactivation of glycogensynthase kinase-3β but not of cyclin-dependent kinase 5 and c-JunNH2-terminal kinase and concomitantly abolishes hyperphosphorylation ofτ:Implications for Alzheimer's disease,” Proc. Nat. Acad. Sci., 99:1140-1145 (2002)].

Androgen receptor agonists can also have a beneficial effect on muscletone and strength. Recent studies have demonstrated that ‘physiologicandrogen replacement in healthy, hypogonadal men is associated withsignificant gains in fat-free mass, muscle size and maximal voluntarystrength,” [S. Bhasin, et al., “Proof of the Effect of Testosterone onSkeletal Muscle,” J. Endocrin., 170: 27-38 (2001)].

Non-steroidal compounds having androgen receptor modulating propertiesare disclosed in U.S. Pat. Nos. 5,688,808; 5,696,130; 6,017,924;6,093,821; WO 01/16139 (published 8 Mar. 2001); and WO 01/16108(published 8 Mar. 2001), all assigned to Ligand Pharmaceuticals, and inWO 01/27086, assigned to Kaken Pharm. Co. Additional background for therationale behind the development of Selective Androgen ReceptorModulators is found in L. Zhi and E. Martinborough in Ann. Rep. Med.Chem. 36: 169-180 (2001). Non-steroidal SARMs were disclosed in J. P.Edwards, “New Nonsteroidal Androgen Receptor Modulators Based on4-(Trifluoromethyl)-2(1H)-Pyrrolidino[3,2-g]quinolinone,” Bioorg. Med.Chem. Lett., 8: 745-750 (1998) and in L. Zhi et al., “Switching AndrogenReceptor Antagonists to Agonists by Modifying C-ring Substituents onPiperidino[3,4-g]quinolinone,” Bioorg. Med. Chem. Lett., 9:1009-1012(1999).

There exists a need for more effective agents that can elicit thepositive responses of androgen replacement therapy without the undesiredside effects of non-tissue selective agonists of the AR. Also needed areandrogenic compounds that exert selective effects on different tissuesof the body. In this invention, we have identified compounds thatfunction as selective androgen receptor modulators (SARMs) using aseries of in vitro cell-assays that profile ligand mediated activationof AR, such as (i) N—C interaction, (ii) transcriptional repression, and(iii) transcriptional activation. SARM compounds in this invention,identified with the methods listed above, exhibit tissue selective ARagonism in vivo, i.e. agonism in bone (stimulation of bone formation ina rodent model of osteoporosis) and antagonism in prostate (minimaleffects on prostate growth in castrated rodents and antagonism ofprostate growth induced by AR agonists).

The compounds of the present invention identified as SARMs are useful totreat diseases or conditions caused by androgen deficiency which can beameliorated by androgen administration. Such compounds are ideal for thetreatment of osteoporosis in women and men as a monotherapy or incombination with inhibitors of bone resorption, such as bisphosphonates,estrogens, SERMs, cathepsin K inhibitors, αvβ3 integrin receptorantagonists, calcitonin, and proton pump inhibitors. They can also beused with agents that stimulate bone formation, such as parathyroidhormone or analogs thereof. The SARM compounds of the present inventioncan also be employed for treatment of prostate disease, such as prostatecancer and benign prostatic hyperplasia (BPH). Moreover, compounds ofthis invention exhibit minimal effects on skin (acne and facial hairgrowth) and can be useful for treatment of hirsutism. Additionally,compounds of this invention can stimulate muscle growth and can beuseful for treatment of sarcopenia and frailty. They can be employed toreduce subcutaneous and visceral abdominal fat in the treatment ofobesity. Moreover, compounds of this invention can exhibit androgenagonism in the central nervous system and can be useful to treatvasomotor symptoms (hot flush) and to increase energy and libido,particularly in postmenopausal women. They can be used asneuroprotective agents in the treatment of Alzheimer's disease. Thecompounds of the present invention can also be used in the treatment ofprostate cancer, either alone or as an adjunct to traditional GnRHagonist/antagonist therapy, for their ability to restore bone, or as areplacement for antiandrogen therapy because of their ability toantagonize androgen in the prostate, and minimize bone depletion in theskeletal system. Further, the compounds of the present invention can beused for their ability to restore bone in the treatment of pancreaticcancer as an adjunct to treatment with antiandrogen, or as monotherapyfor their antiandrogenic properties, offering the advantage overtraditional antiandrogens of being bone-sparing. Additionally, compoundsof this invention can increase the number of blood cells, such as redblood cells and platelets, and can be useful for the treatment ofhematopoietic disorders, such as aplastic anemia. Finally, compounds ofthis invention have minimal effects on lipid metabolism. Thus,considering their tissue selective androgen receptor agonism listedabove, the compounds of this invention are ideal for hormone replacementtherapy in hypogonadic (androgen deficient) men.

SUMMARY OF THE INVENTION

The present invention relates to compounds of structural formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, theiruses and pharmaceutical compositions.

These compounds are effective as androgen receptor agonists and areparticularly effective as selective androgen receptor agonists (SARMs).They are therefore useful for the treatment of conditions caused byandrogen deficiency or which can be ameliorated by androgenadministration.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that are useful as androgenreceptor agonists, in particular, as selective androgen receptoragonists. Compounds of the present invention are described by structuralformula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

-   a is 0 or 1;-   b is 0 or 1;-   R¹ is selected from aryl groups and heterocyclyl groups, wherein    said aryl groups and heterocyclyl groups are optionally substituted    with one or more R⁴ groups;-   R² is selected from

1) —(C═O)NR⁵R⁶,

2) —(C═O)_(a)(C₁₋₁₀)alkyl,

3) —(C═O)_(a)(C₂₋₈)alkenyl,

4) —(C═O)_(a)(C₂₋₈)alkynyl,

5) —(C═O)_(a)(C₃₋₁₀)cycloalkyl,

6) —(C═O)_(a)(C₃₋₈)heterocyclyl, and

7) —(C═O)_(a)aryl,

wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl are each optionally substituted with one or more groupsindependently chosen from R⁴ or two R⁴ groups can, whether or not on thesame atom, be taken together with any attached or intervening atoms towhich they are attached, form a 3-7 membered ring;

-   R³ and R⁴ are each independently selected from:

1) hydrogen,

2) halogen,

3) —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,

4) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl,

5) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,

6) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,

7) —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,

8) —(C═O)_(a)O_(b)aryl,

9) —(C═O)_(a)NR⁵R⁶,

10) —O_(b)(C═O)NR⁵R⁶,

11) —NR⁵(C═O)_(a)O_(b)R^(b),

12) —NR⁵(C═O)NR⁵R⁶,

13) —NR⁵S(O)₂R^(b),

14) —(C═O)OH,

15) trifluoromethoxy,

16) trifluoroethoxy,

17) —O_(b)(C₁₋₁₀)perfluoroalkyl,

18) —S(O)₂O_(b)(C₁₋₁₀)alkyl,

19) —S(O)₂O_(b)(C₂₋₈)alkenyl,

20) —S(O)₂O_(b)(C₂₋₈)alkynyl,

21) —S(O)₂O_(b)(C₃₋₁₀)cycloalkyl,

22) —S(O)₂O_(b)(C₃₋₈)heterocyclyl,

23) —S(O)₂O_(b)aryl,

24) —NR⁵S(O)₂NR⁵R⁶,

25) —CN

26) —NO₂,

27) oxo, and

28) —OH,

wherein said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, and cycloalkylare each optionally substituted with one or more R^(Z) groups;

-   R⁵ and R⁶ are each independently selected from:

1) hydrogen,

2) —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,

3) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl,

4) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,

5) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,

6) —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,

7) —(C═O)_(a)O_(b)aryl,

8) —(C═O) N(R^(b))₂,

9) trifluoromethoxy,

10) trifluoroethoxy,

11) —(C₁₋₁₀)perfluoroalyl,

12) —S(O)₂N(R^(b))₂, and

13) —S(O)₂O_(b) R^(b),

wherein, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynylare optionally substituted with one or more R^(Z) groups, or

-   -   R⁵ and R⁶ can be taken together with the nitrogen to which they        are attached to form a monocyclic or bicyclic heterocycle with        5-7 members in each ring and optionally containing, in addition        to the nitrogen, one or two additional heteroatoms selected from        N, O, and S, wherein said monocylcic or bicyclic heterocycle is        optionally substituted with one or more R^(Z) groups;

-   R^(Z) is selected from:

1) hydrogen,

2) halogen,

3) —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,

4) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl,

5) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,

6) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,

7) —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,

8) —(C═O)_(a)O_(b)aryl,

9) —(C═O)_(a)N(R^(b))₂,

10) —O_(b)(C═O)N(R^(b))₂,

11) —NR^(b)(C═O)_(a)O_(b)R^(b),

12) —NR^(b)(C═O)N(R^(b))₂,

13) —NR^(b)S(O)₂R^(b),

14) —(C═O)OH,

15) trifluoromethoxy,

16) trifluoroethoxy,

17) —O_(b)(C₁₋₁₀)perfluoroalkyl,

18) —S(O)₂O_(b)(C₁₋₁₀)alkyl,

19) —S(O)₂O_(b)(C₂₋₈)alkenyl,

20) —S(O)₂O_(b)(C₂₋₈)alkynyl,

21) —S(O)₂O_(b)(C₃₋₁₀)cycloalkyl,

22) —S(O)₂O_(b)(C₃₋₈)heterocyclyl,

23) —S(O)₂O_(b)aryl,

24) —S(O)₂N(R^(b))₂

25) —NR^(b)S(O)₂N(R^(b))₂

26) —CN,

27) —NO₂,

28) oxo, and

29) —OH,

wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl are each optionally substituted with one or more R^(a)groups;

-   R^(a) is selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H,    CN, O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,    —O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and-   R^(b) is hydrogen, —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,    —(C═O)_(a)O_(b)(C₂₋₈)alkenyl, —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,    —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,    —(C═O)_(a)O_(b)aryl, and (O)₂R^(a); —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,    —S(O)₂N(R^(a))₂, —S(O)₂O_(b)R^(a), trifluoromethoxy,    trifluoroethoxy, or —O_(b)(C₁₋₁₀)perfluoroalkyl,    wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and    heterocyclyl are optionally substituted with up to three    substituents selected from CO₂H, NH₂, OH, (C₁₋₆)alkoxy, halogen, CN,    O(C═O)C₁₋₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,    —O_(b)(C₁₋₁₀)perfluoroalkyl and N(R^(a))₂.

In one embodiment of the invention, the compounds are chosen from thoseof formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

-   a is 0 or 1;-   b is 0 or 1;-   R¹ is selected from aryl groups and heterocyclyl groups, wherein    said aryl groups and heterocyclyl groups are optionally substituted    with one or more R⁴ groups;-   R² is selected from

1) —(C═O)NR⁵R⁶,

2) —(C═O)_(a)(C₁₋₁₀)alkyl,

3) —(C═O)_(a)(C₂₋₈)alkenyl,

4) —(C═O)_(a)(C₂₋₈)alkynyl,

5) —(C═O)_(a)(C₃₋₁₀)cycloalkyl,

6) —(C═O)_(a)(C₃₋₈)heterocyclyl, and

7) —(C═O)_(a)aryl,

wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl are each optionally substituted with one or more groupsindependently chosen from R⁴ or two R⁴ groups can, whether or not on thesame atom, be taken together with any attached or intervening atoms towhich they are attached, form a 5-7 membered ring;

-   R³ and R⁴ are each independently selected from:

1) hydrogen,

2) halogen,

3) —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,

4) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl,

5) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,

6) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,

7) —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,

8) —(C═O)_(a)O_(b)aryl,

9) —(C═O)_(a)NR⁵R⁶,

10) —O_(b)(C═O)NR⁵R⁶,

11) —NR⁵(C═O)_(a)O_(b)R^(b),

12) —NR⁵(C═O)NR⁵R⁶,

13) —NR⁵S(O)₂R^(b),

14) —(C═O)OH,

15) trifluoromethoxy,

16) trifluoroethoxy,

17) —O_(b)(C₁₋₁₀)perfluoroalkyl,

18) —S(O)₂O_(b)(C₁₋₁₀)alkyl,

19) —S(O)₂O_(b)(C₂₋₈)alkenyl,

20) —S(O)₂O_(b)(C₂₋₈)alkynyl,

21) —S(O)₂O_(b)(C₃₋₁₀)cycloalkyl,

22) —S(O)₂O_(b)(C₃₋₈)heterocyclyl,

23) —S(O)₂O_(b)aryl,

24) —NR⁵S(O)₂NR⁵R⁶,

25) —CN

26) —NO₂,

27) oxo, and

28) —OH,

wherein said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, and cycloalkylare each optionally substituted with one or more R^(Z) groups;

-   R⁵ and R⁶ are each independently selected from:

1) hydrogen,

2) —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,

3) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl,

4) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,

5) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,

6) —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,

7) —(C═O)_(a)O_(b)aryl,

8) —(C═O) N(R^(b))₂,

9) trifluoromethoxy,

10) trifluoroethoxy,

11) —(C₁₋₁₀)perfluoroalkyl,

12) —S(O)₂N(R^(b))₂, and

13) —S(O)₂O_(b) R^(b),

wherein, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynylare optionally substituted with one or more R^(z) groups, or

-   -   R⁵ and R⁶ can be taken together with the nitrogen to which they        are attached to form a monocyclic or bicyclic heterocycle with        5-7 members in each ring and optionally containing, in addition        to the nitrogen, one or two additional heteroatoms selected from    -   N, O, and S, wherein said monocylcic or bicyclic heterocycle is        optionally substituted with one or more R^(z) groups;

-   R⁷ is selected from:

1) hydrogen,

2) halogen,

3) —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,

4) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl,

5) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,

6) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,

7) —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,

8) —(C═O)_(a)O_(b)aryl,

9) —(C═O)_(a)N(R^(b))₂,

10) —O_(b)(C═O)N(R^(b))₂,

11) —NR^(b)(C═O)_(a)O_(b)R^(b),

12) —NR^(b)(C═O)N(R^(b))₂,

13) —NR^(b)S(O)₂R^(b),

14) —(C═O)OH,

15) trifluoromethoxy,

16) trifluoroethoxy,

17) —O_(b)(C₁₋₁₀)perfluoroalkyl,

18) —S(O)₂O_(b)(C₁₋₁₀)alkyl,

19) —S(O)₂O_(b)(C₂₋₈)alkenyl,

20) —S(O)₂O_(b)(C₂₋₈)alkynyl,

21) —S(O)₂O_(b)(C₃₋₁₀)cycloalkyl,

22) —S(O)₂O_(b)(C₃₋₈)heterocyclyl,

23) —S(O)₂O_(b)aryl,

24) —S(O)₂N(R^(b))₂

25) —NR^(b)S(O)₂N(R^(b))₂

26) —CN,

27) —NO₂,

28) oxo, and

29) —OH,

wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl are each optionally substituted with one or more R^(a)groups;

-   R^(a) is selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H,    CN, O(C═O)C₁₋₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,    —O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and-   R^(b) is hydrogen, —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,    —(C═O)_(a)O_(b)(C₂₋₈)alkenyl, —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,    —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,    —(C═O)_(a)O_(b)aryl, and (O)₂R^(a); —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,    —S(O)₂N(R^(a))₂, —S(O)₂O_(b)R^(a), trifluoromethoxy,    trifluoroethoxy, or —O_(b)(C₁₋₁₀)perfluoroalkyl, wherein said alkyl,    alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl are optionally    substituted with up to three substituents selected from CO₂H, NH₂,    OH, (C₁₋₆)alkoxy, halogen, CN, NO₂, O(C═O)C₁₋₆ alkyl,    trifluoromethoxy, trifluoroethoxy, —O_(b)(C₁₋₁₀)perfluoroalkyl and    N(R^(a))₂.

In one embodiment of the present invention, R¹ is selected from thienyl,phenyl, naphthyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzoxazolyl, benzothiazolyl, benzodihydrofuranyl, 1,3-benzodioxilyl,2,3-dihydro-1,4-benzodioxinyl, indolyl, quinolyl, isoquinolyl, furanyl,imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazol, isoindolyl,pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolinyl,pyrazolinyl, thiadiazolyl, oxadiazolyl, and triazolyl, further whereinR¹ is optionally substituted with one or more R⁴ groups.

In a class of this embodiment, R¹ is selected from thiazolyl, pyridinyl,pyrozolinyl, pyrimidinyl, pyrrolyl, napthyl, pyrazolyl, thienyl,isoxazolyl, and oxazolyl. In a subclass, R¹ is selected from thiazol4-yl, thiazol 5-yl, pyrazol 3-yl, pyrazol 4-yl, 2-pyridyl, pyrazolinyl,oxazol 5-yl, and oxazol 4-yl. In both these embodiments R¹ is optionallysubstituted with one or more R⁴ groups.

In one embodiment of the invention, R³ and R⁴ are each independentlyselected from: hydrogen, halogen, —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl,—(C═O)_(a)O_(b)(C₂₋₈)alkenyl, —(C═O)_(a)O_(b)(C₂₋₈)alkynyl,—(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,—(C═O)_(a)O_(b)aryl, —(C═O)_(a)NR⁵R⁶, —NR⁶S(O)₂R^(b), trifluoroethoxy,—O_(b)(C₁₋₁₀)perfluoroalkyl, —S(O)₂O_(b)(C₁₋₁₀)alkyl,—S(O)₂O_(b)(C₃₋₁₀)cycloalkyl, —CN, oxo, and —OH, wherein said aryl,alkyl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl are eachoptionally substituted with one or more R^(z) groups.

In another embodiment, R⁵ and R⁶ are each independently selected from:hydrogen, —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,—(C═O)_(a)O_(b) (C₃₋₈)heterocyclyl, —(C═O)_(a)O_(b)aryl, —(C═O)N(R^(b))₂, and (C₁₋₁₀)perfluoroalkyl, further wherein, said alkyl,cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl are optionallysubstituted with one or more R^(z) groups, or R⁵ and R⁶ can be takentogether with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O, and S, wherein saidmonocylcic or bicyclic heterocycle is optionally substituted with one ormore R^(z) groups.

In yet another embodiment, R^(b) is selected from hydrogen,—(C═O)_(a)O_(b) (C₁₋₆)alkyl, —(C═O)_(a)O_(b) (C₃₋₆)cycloalkyl,—(C═O)_(a)O_(b) (C₃₋₆)heterocyclyl, —(C═O)_(a)O_(b) aryl,(C₁₋₃)perfluoroalkyl, and wherein said alkyl, cycloalkyl, aryl, andheterocyclyl are optionally substituted with up to two substituentsselected from NH₂, OH, (C₁₋₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁₋₆alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,—O_(b)(C₁₋₁₀)perfluoroalkyl and N(R^(a))₂.

In one variant of the invention, R² is —(C═O)NR⁵R⁶. In yet anothervariant of the invention, R² is —(C═O)_(a)(C₁₋₁₀)alkyl,—(C═O)_(a)(C₂₋₈)alkenyl, —(C═O)_(a)(C₂₋₈)alkynyl,—(C═O)_(a)(C₃₋₁₀)cycloalkyl, —(C═O)_(a)(C₃₋₈)heterocyclyl, and—(C═O)_(a)aryl. In these variants of the invention said aryl, alkyl,alkenyl, alkynyl, heterocyclyl, and cycloalkyl are each optionallysubstituted with one or more groups independently chosen from R⁴ or twoR⁴ groups can, whether or not on the same atom, be taken together withany attached or intervening atoms to which they are attached, form a 5-7membered ring.

In yet another embodiment of the compounds of the present invention, R¹is an imidazole having a hydrogen atom at the nitrogen in position oneof the imidazolyl ring. In an additional embodiment, R¹ is other than anunstaturated 6-membered ring substituted with a —SO₂NHaryl or—SO₂NHheterocyclyl.

In another embodiment, R¹ is thiazolyl and R² is other than (C₁₋₆)alkyl,phenyl(C₁₋₆)alkyl, or phenoxy(C₁₋₆)alkyl, optionally substituted with atleast one halogen.

In yet another embodiment of the invention, when R¹ is imidazolinyl orimidazolyl, the carbon in the 2 position of the ring, is not substitutedwith (C₁₋₁₅)alkyl having up to three carbons replaced by N, O, or S.

In yet another embodiment, R² is other than a group selected from H,unsubstituted —(C═O)(C₁₋₆)alkyl, unsubstituted —(C═O)phenyl, orunsubstituted —C═O)benzyl.

In another embodiment, when R² is —(C═O)NR⁵R⁶ and R⁵ is hydrogen; R⁶ isother than (C₁₋₆)alkyl optionally substituted by a group selected fromphenyl and phenoxy which is optionally halogen-substituted.

Illustrative but nonlimiting examples of compounds of the presentinvention are the following:

-   N-isopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-[(1R)-1-phenylpropyl]-N′-[2-(1,3-thiazol-4-yl)-1H-Benzimidazol-5-yl]urea;-   N-(3,5-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-Benzimidazol-5-yl]urea;-   N-benzyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-butyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(2-phenylethyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(2-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(2-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(2-chlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-[(1S)-1-phenylethyl]-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(3-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(4-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(4-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(2,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(3,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(4-methoxyphenyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-(3-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   N-(4-bromobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   N-(4-methoxybenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   6-({[(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-1H-benzimidazole;-   6-[({[(1R)-1-phenylethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-[({[1-(1-naphthyl)ethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3,5-difluorophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   N-methyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-benzyl-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;-   N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]-3,4-dihydroquinoline-1(2H)-carboxamide;-   N-ethyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   6-({[methyl(2-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[methyl(4-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   N-(4-hydroxyphenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(2-hydroxyethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(4-hydroxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   N-(2-chlorophenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(4-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(2-cyanoethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-[({methyl[4-(trifluoromethoxy)phenyl]-amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[benzyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[methyl(1-naphthyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[phenyl(1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[cyclohexyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   N-(1-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   N-(4-chlorophenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-Benzimidazol-5-yl]urea;-   6-({[(1-methyl-1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;-   6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-[({[(1S)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(2,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H    benzimidazole;-   2-(1,3-thiazol-4-yl)-6[({[3(trifluoromethyl)benzyl]amino}carbonyl)amino]-3H-benzimidazole;-   6-({[(benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-[({methyl[(1R)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-[({methyl[(1S)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-{[(phenylpyrrolidin-1-yl)carbonyl]amino}-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(2-phenylcyclopropyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(4-methoxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(5-isopropyl-2-methylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(6-methoxypyridinium-2-yl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;-   6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3,4-dichlorobenzyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-[({[(2-bromothien-3-yl)methyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-[({methyl[5-(trifluoromethyl)-1,3,4-thiadiazol-3-ium-2-yl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(2,4-dichlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   N-cyclopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   N-[4(hydroxymethyl)phenyl]-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea;-   1-[2-(3-Fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea;-   2-Pyridin-2-yl-3H-benzoimidazol-5-ylamine;-   2-Oxazol-4-yl-3H-benzoimidazol-5-ylamine;-   2-(1H-Pyrazol-3-yl)-3H-benzoimidazol-5-ylamine;-   2-(1-Methyl-1H-pyrazol-3-yl)-3H-benzoimidazol-5-ylamine; and    pharmaceutically acceptable salts and stereoisomers thereof.

In one embodiment of this invention is a compound chosen from:

-   N-(3-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;-   N-(3,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   N-benzyl-N-methyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   N-ethyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;-   6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[isopropyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-yl)-3H-benzimidazole;-   6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;-   N-cyclopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   1-[2-(3-Fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea;    and    pharmaceutically acceptable salts and stereoisomers thereof.

Other non-limiting examples of the compounds of formula I include:

-   6-({[(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-1H-benzimidazol-1-ium    trifluoroacetate;-   6-[({[(1R)-1-phenylethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({[1-(1-naphthyl)ethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3,5-difluorophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[methyl(2-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[methyl(4-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(2-hydroxyethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(4-hydroxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(4-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(2-cyanoethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({methyl[4-(trifluoromethoxy)phenyl]-amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[benzyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[methyl(1-naphthyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[phenyl(1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[cyclohexyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(1-methyl-1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({[(1S)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(2,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H    benzimidazol-1-ium trifluoroacetate;-   2-(1,3-thiazol-4-yl-6[({[3(trifluoromethyl)benzyl]amino}carbonyl)amino]-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-1-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({methyl[(1R)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({methyl[(1S)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-{[(2-phenylpyrrolidin-1-yl)carbonyl]amino}-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(2-phenylcyclopropyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(4-methoxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(5-isopropyl-2-methylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(6-methoxypyridinium-2-yl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    bis(trifluoroacetate);-   6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3,4-dichlorobenzyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({[(2-bromothien-3-yl)methyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({methyl[5-(trifluoromethyl)-1,3,4-thiadiazol-3-ium-2-yl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    bis(trifluoroacetate);-   6-({[(2,4-dichlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate; and stereoisomers thereof.

In one embodiment of the invention, the compounds are selected from:

-   6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[isopropyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-[({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;    and stereoisomers thereof.

Other illustrative but nonlimiting examples of compounds of the presentinvention include:

-   3-Phenyl-N-(2-thiazolyl-3H-benzoimidazol-5-yl)-propionamide;-   2-Phenoxy-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-acetamide;-   trans-5-{[1-(2-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazolyl-3H-benzoimidazole;-   5-(4-Phenyl-butanoylamino)-2-thiazol-4-yl-3H-benzoimidazole;-   6-(3-Phenyl-butanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid    (2-thiazolyl-3H-benzoimidazol-5-yl)-amide;-   (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide;-   2-Methyl-3-phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide;-   5-(2-Phenyl-butanoylamino)-2-thiazol-4-yl-3H-benzoimidazole;-   5-{[1-(1-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol-4-yl-3H-benzoimidazole;-   5-(2,3-Diphenyl-propanoylamino)-2-thiazol-4-yl-3H-benzoimidazole;-   5-(2,2-Diphenyl-ethanoylamino)-2-thiazol-4-yl-3H-benzoimidazole;-   5-(3-Cyclohexyl-propanoylamino)-2-thiazol-4-yl-3H-benzoimidazole;-   5-(2-Bicyclo[2.2.1]hept-2-yl-ethanoylamino)-2-thiazol-4-yl-3H-benzoimidazole;-   5-(2-Methyl-2-phenyl-propanoylamino)-2-thiazolyl-1H-benzoimidazole;-   5-(2-Phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   5-(2-Methoxy-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   5-(2-Hydroxy-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   6-(2-Hydroxy-2-phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   6-(2-Indan-2-yl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   6-[(1-Indan-1-yl-methanoyl)-amino]-2-thiazol-4-yl-1H-benzoimidazole;-   6-(2-Cyclopentyl-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   6-(2-Cyclohexyl-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   6-[2-(3,4-Dichloro-phenyl)-ethanoylamino]-2-thiazol-4-yl-1H-benzoimidazole;-   6-{[1-(1-Phenyl-cyclopentyl)-methanoyl]-amino}-2-thiazol-4-yl-1H-benzoimidazole;-   6-(3,3-Diphenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   6-(2-Biphenyl-4-yl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   (3S)-3-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-butyramide;-   (3R)-3-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-butyramide;-   6-[2-(3-Fluoro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   2-(3-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   6-[2-(3-Methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-(4-trifluoromethyl-phenyl)-acetamide;-   N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-p-tolyl-acetamide;-   6-[2-(4-Nitro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-(3-trifluoromethyl-phenyl)-acetamide;-   6-[2-(3-Nitro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   6-[2-(4-Fluoro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   6-[2-(Bis-trifluoromethyl-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   2-(4-Chloro-phenyl)-N-(2-thiazolyl-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   2-(3,4-Difluoro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   6-[2-(4-Methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   2-(3,5-Dimethyl-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   2-(3,5-Difluoro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   6-[2-(4-Isopropyl-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   6-[2-(3-Fluoro-4-methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-(3,4,5-trifluoro-phenyl)-acetamide;-   2-(4-Nitro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide;-   6-[2-(4-Hydroxy-phenyl)-propanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   2-(4-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide;-   6-(2-Benzo[1,3]dioxol-5-yl-ethanoylamino)-2-thiazol-4-yl-3H-benzoimidazole;-   2-(4-Chloro-phenyl)-2-hydroxy-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-(4-Chloro-phenyl)-2-hydroxy-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   (2S)-2-(4-Chloro-phenyl)-2-hydroxy-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   (2R)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2S)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   3-(3-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-Hydroxy-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide;-   (2S)-2-Hydroxy-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide;-   2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2S)-2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   3-(3-Chlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   3-(4-Methylphenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   3-(3-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   3-(4-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   3-(4-Chlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   3-(2-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   3-(4-Methylphenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   2-(4-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]propanamide;-   1-(4-Chlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide;-   1-(3-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide;-   1-(3-Chlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide;-   1-(3,5-Dichlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide;-   1-(3,5-Difluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide;-   2-Hydroxy-3-methyl-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   (2R)-2-Hydroxy-3-methyl-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   (2S)-2-Hydroxy-3-methyl-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   2-Cyclopropyl-2-hydroxy-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]acetamide;-   2-(3-Chlorophenyl)-2-hydroxy-3-methyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   (2R)-2-(3-Chlorophenyl)-2-hydroxy-3-methyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;-   (2S)-2-(3-Chlorophenyl)-2-hydroxy-3-methyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide;    and    pharmaceutically acceptable salts and stereoisomers thereof.

In another embodiment of this invention is a compound chosen from:

-   3-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide;-   trans-5-{[1-(2-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol-4-yl-3H-benzoimidazole;-   6-(3-Phenyl-butanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid    (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide;-   (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide;-   2-Methyl-3-phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide;-   5-(2-Phenyl-butanoylamino)-2-thiazol-4-yl-3H-benzoimidazole;-   5-{[1-(1-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol-4-yl-3H-benzoimidazole;-   6-(2-Phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Hydroxy-2-phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   6-(2-Indan-2-yl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazole;-   (3S)-3-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-butyramide;-   (3R)-3-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-butyramide;-   6-[2-(3-Fluoro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazole;-   2-(3-Chloro-phenyl)-N-(2-thiazolyl-1H-benzoimidazol-5-yl)-acetamide;-   2-(3,5-Dimethyl-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   2-(3,5-Difluoro-phenyl)-N-(2-thiazolyl-1H-benzoimidazol-5-yl)-acetamide;-   N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-(3,4,5-trifluoro-phenyl)-acetamide;-   2-(4-Nitro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide;-   2-(4-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide;-   3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-(4-Chloro-phenyl)-2-hydroxy-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   (2S)-2-(4-Chloro-phenyl)-2-hydroxy-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;-   (2R)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2S)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   3-(3-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-Hydroxy-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide-   2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2S)-2-(4-Chlorophenyl)-3-methyl-N-(2-thiazolyl-1H-benzoimidazol-5-yl)-butyramide;    and    pharmaceutically acceptable salts and stereoisomers thereof.

Non-limiting examples of salts are selected from:

-   trans-5-{[1-(2-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate-   5-(4-Phenyl-butanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(3-Phenyl-butanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-(2-Phenyl-butanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-{[1-(1-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazolyl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-(2,3-Diphenyl-propanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-(2,2-Diphenyl-ethanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-(3-Cyclohexyl-propanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-(2-Bicyclo[2.2.1]hept-2-yl-ethanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoroacetate;-   6-(2-Methyl-2-phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Methoxy-2-phenyl-ethanoylamino)-2-thiazolyl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Hydroxy-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Hydroxy-2-phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Indan-2-yl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[(1-Indan-1-yl-methanoyl)-amino]-2-thiazolyl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Cyclopentyl-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Cyclohexyl-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2(3,4-Dichloro-phenyl)-ethanoylamino]-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-{[1-(1-Phenyl-cyclopentyl)-methanoyl]-amino}-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(3,3-Diphenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Biphenyl-4-yl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(3-Fluoro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(3-Methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(4-Nitro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(3-Nitro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(4-Fluoro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(Bis-trifluoromethyl-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(4-Methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(4-Isopropyl-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(3-Fluoro-4-methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(4-Hydroxy-phenyl)-propanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Benzo[1,3-]dioxol-5-yl-ethanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;    and stereoisomers thereof.

In one embodiment of the invention the compounds of formula I areselected from:

-   trans-5-{[1-(2-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate-   6-(3-Phenyl-butanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-(2-Phenyl-butanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-{[1-(1-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Hydroxy-2-phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-(2-Indan-2-yl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   6-[2-(3-Fluoro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;    and stereoisomers thereof.

In yet another embodiment of the invention the compound of formula I isselected from:

-   N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   N-(1-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   N-methyl-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea;-   trans-5-{[1-(2-Phenyl-cyclopropyl)-methanoyl]-amino}    -2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate;-   (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid    (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide;-   (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide;-   5-(2-Phenyl-butanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-{[1-(1-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   (2R)-2-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-butyramide;-   3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2S)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   3-(3-Chloro-phenyl)-N-(2-thiazolyl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-Hydroxy-2-phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide;-   (2S)-2-Hydroxy-2-phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide;    and-   2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide.

In another embodiment of the invention, the compound is selected from:

-   N-(1-phenylcyclopropyl)-N″-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;-   trans-5-{[1-(2-Phenyl-cyclopropyl)-methanoyl]    -amino}-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   (1R,2R)-2-Phenyl-cyclopropanecarboxylic acid    (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide;-   (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide;-   5-(2-Phenyl-butanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   5-{[1-(1-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol-4-yl-3H-benzoimidazol-1-ium;    2,2,2-trifluoro-acetate;-   (2R)-2-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-butyramide;-   3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2S)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide;-   (2R)-2-Hydroxy-2-phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide;-   (2S)-2-Hydroxy-2-phenyl-N-(2-thiazolyl-3H-benzoimidazol-5-yl)-propionamide;    and-   2-(4Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide.

In yet another embodiment, the compound is selected from:

-   N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-6-yl]urea;-   6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium    trifluoroacetate;-   N-methyl-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea;    and-   3-(3-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide.

The compounds of the present invention can have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein can exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof.

The term “alkyl” shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term“C₀ alkyl” (as in “C₀₋₈ alkylaryl”) shall refer to the absence of analkyl group.

The term “alkenyl” shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds can bepresent. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group can contain triple bonds and can be substituted if asubstituted alkynyl group is indicated.

“Cycloalkyl” as used herein is intended to include non-aromatic cyclichydrocarbon groups, having the specified number of carbon atoms, whichmay or may not be bridged or structurally constrained. Examples of suchcycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, cycloheptyl,tetrahydro-naphthalene, methylenecylohexyl, and the like. As usedherein, examples of “C₃-C₁₀ cycloalkyl” can include, but are not limitedto:

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

“Perfluoroalkyl” represents alkyl chains of up to 10 carbon atoms havingexhaustive substitution of their corresponding hydrogens with fluorineatoms.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthrylor acenaphthyl. In cases where the aryl substituent is bicyclic and onering is non-aromatic, it is understood that attachment is via thearomatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms chosen from O, N and S.Heteroaryl groups within the scope of this definition include but arenot limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl,pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl,pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrahydroquinoline. As with the definition of heterocycle below,“heteroaryl” is also understood to include the N-oxide derivative of anynitrogen-containing heteroaryl.

In cases where the heteroaryl substituent is bicyclic and one ring isnon-aromatic or contains no heteroatoms, it is understood thatattachment is via the aromatic ring or via the heteroatom containingring, respectively.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), it shall beinterpreted as including those limitations given above for “alkyl” and“aryl.” Designated numbers of carbon atoms (e.g., C₀₋₈) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo. The term“heterocycle” or “heterocyclyl” as used herein is intended to mean a 5-to 10-membered aromatic or nonaromatic heterocycle containing from 1 to4 heteroatoms selected from the group consisting of O, N and S, andincludes bicyclic groups. “Heterocyclyl” therefore includes the abovementioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

The terms “arylalkyl” and “alkylaryl” include an alkyl portion wherealkyl is as defined above and include an aryl portion where aryl is asdefined above. Examples of arylalkyl include, but are not limited to,benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, andthienylpropyl. Examples of alkylaryl include, but are not limited to,toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

In certain instances, R⁵ and R⁶ are defined such that they can be takentogether with the nitrogen to which they are attached to form amonocyclic or bicyclic heterocycle with 5-7 members in each ring andoptionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, wherein saidheterocycle is optionally substituted with one or more substituentsselected from R^(Z). Examples of the heterocycles that can thus beformed include, but are not limited to the following, keeping in mindthat the heterocycle is optionally substituted with one or moresubstituents chosen from R^(Z):

The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur(S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

When any variable (e.g., R⁵, R⁶, etc.) occurs more than one time in anysubstituent or in formula I, its definition in each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², R³,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity.

Lines drawn into the ring systems from substituents indicate that theindicated bond can be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups can be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases one embodiment will have fromzero to three substituents.

Compounds of the present invention have been found to betissue-selective modulators of the androgen receptor (SARMs). In oneaspect, compounds of the present invention can be useful to activate thefunction of the androgen receptor in a mammal, and in particular toactivate the function of the androgen receptor in bone and/or muscletissue and block or inhibit (“antagonize”) the function of the androgenreceptor in the prostate of a male individual or in the uterus of afemale individual.

A further aspect of the present invention is the use of compounds offormula I to attenuate or block the function of the androgen receptor inthe prostate of a male individual or in the uterus of a femaleindividual induced by AR agonists, but not in hair-growing skin or vocalcords, and activate the function of the androgen receptor in bone and/ormuscle tissue, but not in organs which control blood lipid levels (e.g.liver).

The compounds of the present invention can be used to treat conditionswhich are caused by androgen deficiency, which can be ameliorated byandrogen replacement, or which can be increased by androgen replacement,including, but not limited to osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, bone fracture,such as for example, vertebral and non-vertebral fractures, bone damagefollowing bone reconstructive surgery, sarcopenia, frailty, aging skin,male hypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and otherhematopoietic disorders, arthritic condition and joint repair,HIV-wasting, Alzheimer's disease, prostate cancer, cancer cachexia,muscular dystrophies, Alzheimer's disease, premature ovarian failure,and autoimmune disease, alone or in combination with other activeagents. Treatment is effected by administration of a therapeuticallyeffective amount of a compound of structural formula I to a mammal inneed of such treatment. In addition, these compounds are useful asingredients in pharmaceutical compositions alone or in combination withother active agents.

In one embodiment, the compounds of the present invention can be used totreat conditions in a male individual which are caused by androgendeficiency or which can be ameliorated by androgen replacement,including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, HIV-wasting,prostate cancer, cancer cachexia, obesity, arthritic conditions,anemias, such as for example, aplastic anemia, muscular dystrophies, andAlzheimer's disease, alone or in combination with other active agents.Treatment is effected by administration of a therapeutically effectiveamount of a compound of structural formula I to a male individual inneed of such treatment.

“Arthritic condition” or “arthritic conditions” refers to a diseasewherein inflammatory lesions are confined to the joints or anyinflammatory conditions of the joints, most notably osteoarthritis andrheumatoid arthritis (Academic Press Dictionary of Science Technology;Academic Press; 1st edition, Jan. 15, 1992). The compounds of Formula Iare also useful, alone or in combination, to treat or prevent arthriticconditions, such as Behcet's disease; bursitis and tendinitis; CPPDdeposition disease; carpal tunnel syndrome; Ehlers-Danlos syndrome;fibromyalgia; gout; infectious arthritis; inflammatory bowel disease;juvenile arthritis; lupus erythematosus; lyme disease; marfan syndrome;myositis; osteoarthritis; osteogenesis imperfecta; osteonecrosis;polyarteritis; polymyalgia rheumatica; psoriatic arthritis; Raynaud'sphenomenon; reflex sympathetic dystrophy syndrome; Reiter's syndrome;rheumatoid arthritis; scleroderma; and Sjogren's syndrome. An embodimentof the invention encompasses the treatment or prevention of an arthrticcondition which comprises administering a therapeutically effectiveamount of a Compound of Formula I. A subembodiment is the treatment orprevention of osteoarthritis which comprises administering atherapeutically effective amount of a Compound of Formula I. See: CutoloM, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A. Ann. N.Y.Acad. Sci. 2002 June; 966:131-42; Cutolo, M. Rheum Dis Clin North Am2000 November; 26(4):881-95; Bijlsma J W, Van den Brink H R. Am J ReprodImmunol 1992 October-December; 28(3-4):231-4; Jansson L, Holmdahl R.;Arthritis Rheum 2001 September; 44(9):2168-75; and Purdie D W. Br MedBull 2000; 56(3):809-23. Also, see Merck Manual, 17th edition, pp.449-451.

When used in combination to treat arthritic conditions, the Compounds ofFormula I can be used with any of the drugs diclosed herein as usefulfor combination therapy, or can be used with drugs known to treat orprevent arrthritic conditions, such as corticosteroids, cytoxic drugs(or other disease modifying or remission inducing drugs), goldtreatment, methotrexate, NSAIDs, and COX-2 inhibitors.

In another embodiment, the compounds of the present invention can beused to treat conditions in a female individual which are caused byandrogen deficiency or which can be ameliorated by androgen replacement,including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, postmenopausal symptoms,periodontal disease, HIV-wasting, cancer cachexia, obesity, anemias,such as for example, aplastic anemia, muscular dystrophies, Alzheimer'sdisease, premature ovarian failure, and autoimmune disease, alone or incombination with other active agents. Treatment is effected byadministration of a therapeutically effective amount of a compound ofstructural formula I to a female individual in need of such treatment.

The compounds of formula I are also useful in the enhancement of muscletone in mammals, such as for example, humans.

The compounds of structural formula I can also be employed as adjunctsto traditional androgen depletion therapy in the treatment of prostatecancer to restore bone, minimize bone loss, and maintain bone mineraldensity. In this manner, they can be employed together with traditionalandrogen deprivation therapy, including GnRH agonists/antagonists, suchas those disclosed in P. Limonta, et al., “LHRH analogues as anticanceragents: pituitary and extrapituitary sites of action,” Exp. Opin.Invest. Drugs, 10: 709-720 (2001); H. J. Stricker, “Luteinizinghormone-releasing hormone antagonists,” Urology, 58 (Suppl. 2A): 24-27(2001); R. P. Millar, et al., “Progress towards the development ofnon-peptide orally-active GnRH antagonists,” British Medical Bulletin,56: 761-772 (2000); and A. V. Schally et al., “Rational use of agonistsand antagonists of LH-RH in the treatment of hormone-sensitive neoplasmsand gynecologic conditions,” Advanced Drug Delivery Reviews, 28: 157-169(1997). The compounds of structural formula I can be used in combinationwith antiandrogens, such as flutamide, 2-hydroxyflutamide (the activemetabolite of flutamide), nilutamide, and bicalutamide (Casodex™) in thetreatment of prostate cancer.

Further, the compounds of the present invention can also be employed inthe treatment of pancreatic cancer, either for their androgen antagonistproperties or as an adjunct to an antiandrogen, such as flutamide,2-hydroxyflutamide (the active metabolite of flutamide), nilutamide, andbicalutamide (Casodex™).

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

Compounds of structural formula I can minimize the negative effects onlipid metabolism. Therefore, considering their tissue selective androgenagonistic properties, the compounds of this invention exhibit advantagesover existing approaches for hormone replacement therapy in hypogonadic(androgen deficient) male individuals.

Additionally, compounds of the present invention can increase the numberof blood cells, such as red blood cells and platelets, and can be usedfor treatment of hematopoietic disorders, such as aplastic anemia.

Representative compounds of the present invention typically displaysubmicromolar binding affinity for the androgen receptor. Compounds ofthis invention are therefore useful in treating mammals suffering fromdisorders related to androgen receptor function. Therapeuticallyeffective amounts of the compound, including the pharmaceuticallyacceptable salts thereof, are administered to the mammal, to treatdisorders related to androgen receptor function, or which can beimproved by the addition of additional androgen, such as for example,osteoporosis, periodontal disease, bone fracture, bone damage followingbone reconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, hematopoietic disorders,such as for example, aplastic anemia, pancreatic cancer, Alzheimer'sdisease, inflammatory arthritis, and joint repair.

The compounds of the present invention can be administered in theirenantiomerically pure form. Racemic mixtures can be separated into theirindividual enantiomers by any of a number of conventional methods. Theseinclude chiral chromatography, derivatization with a chiral auxiliaryfollowed by separation by chromatography or crystallization, andfractional crystallization of diastereomeric salts.

As used herein, a compound of the present invention which functions asan “agonist” of the androgen receptor can bind to the androgen receptorand initiate a physiological or a pharmacological responsecharacteristic of that receptor. The term “tissue-selective androgenreceptor modulator” refers to an androgen receptor ligand that mimicsthe action of a natural ligand in some tissues but not in others. A“partial agonist” is an agonist which is unable to induce maximalactivation of the receptor population, regardless of the amount ofcompound applied. A “full agonist” induces full activation of theandrogen receptor population at a given concentration. A compound of thepresent invention which functions as an “antagonist” of the androgenreceptor can bind to the androgen receptor and block or inhibit theandrogen-associated responses normally induced by a natural androgenreceptor ligand.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Non-limitingrepresentive salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. In one variantof the invention, the salts are chosen from the ammonium, calcium,lithium, magnesium, potassium, and sodium salts. Non-limiting examplesof salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidinei glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,metbylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts can beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Representative acids which can be employedinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic,phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonicacid, trifluoroacetic acid, and the like. In one variant, the acids areselected from citric, fumaric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” it is meant that the carrier, diluentor excipient must be compatible with the other ingredients of theformulation and not be deleterious to the recipient thereof.

The terms “administration of a compound” and “administering a compound”should be understood to mean providing a compound of the invention or aprodrug of a compound of the invention to the individual in need oftreatment.

By the term “modulating a function mediated by the androgen receptor ina tissue selective manner” is meant modulating a function mediated bythe androgen receptor selectively (or discriminately) in anabolic (boneand/or muscular) tissue (bone and muscular) in the absence of suchmodulation at androgenic (reproductive) tissue, such as the prostate,testis, seminal vesicles, ovary, uterus, and other sex accessorytissues. In one embodiment the function of the androgen receptor inanabolic tissue is activated whereas the function of the androgenreceptor in androgenic tissue is blocked or suppressed.

The administration of a compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well-known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration, other drugs and treatments which the patientcan concomitantly require, and other factors in the physician'sjudgment.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention can alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

Generally, the daily dosage of a compound of structural formula I can bevaried over a wide range from 0.01 to 1000 mg per adult human per day.For example, dosages range from 0.1 to 200 mg/day. For oraladministration, the compositions can be provided in the form of tabletscontaining 0.01 to 1000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5,3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175, 180, 200,225, and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the mammal to be treated.

The dose can be administered in a single daily dose or the total dailydosage can be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose can be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through an intravenous solution, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

Formulations of the tissue-selective androgen receptor modulatoremployed in the present method for medical use comprise a compound ofstructural formula I together with an acceptable carrier thereof andoptionally other therapeutically active ingredients. The carrier must bepharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not being deleterious to therecipient subject of the formulation.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of structural formula I together witha pharmaceutically acceptable carrier thereof.

The formulations include those suitable for oral, rectal, intravaginal,topical or parenteral (including subcutaneous, intramuscular andintravenous administration). In one embodiment, the formulations arethose suitable for oral administration.

The formulations can be presented in a unit dosage form and can beprepared by any of the methods known in the art of pharmacy. All methodsinclude the step of bringing the active compound in association with acarrier which constitutes one or more ingredients. In general, theformulations are prepared by uniformly and intimately bringing theactive compound in association with a liquid carrier, a waxy solidcarrier or a finely divided solid carrier, and then, if needed, shapingthe product into the desired dosage form.

Formulations of the present invention suitable for oral administrationcan be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension or solution in an aqueousliquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.

A tablet can be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets can be prepared bycompressing in a suitable machine the active compound in a free flowingform, e.g., a powder or granules, optionally mixed with accessoryingredients, e.g., binders, lubricants, inert diluents, disintegratingagents or coloring agents. Molded tablets can be made by molding in asuitable machine a mixture of the active compound, preferably inpowdered form, with a suitable carrier. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethyl-cellulose,polyethylene glycol, waxes and the like. Non-limiting representativelubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Oral liquid forms, such as syrups or suspensions in suitably flavoredsuspending or dispersing agents such as the synthetic and natural gums,for example, tragacanth, acacia, methyl cellulose and the like, can bemade by adding the active compound to the solution or suspension.Additional dispersing agents which can be employed include glycerin andthe like.

Formulations for vaginal or rectal administration can be presented as asuppository with a conventional carrier, i.e., a base that is nontoxicand nonirritating to mucous membranes, compatible with a compound ofstructural formula I, and is stable in storage and does not bind orinterfere with the release of the compound of structural formula I.Suitable bases include: cocoa butter (theobroma oil), polyethyleneglycols (such as carbowax and polyglycols), glycol-surfactantcombinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acidesters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, andhydrogenated vegetable oils. When glycerinated gelatin suppositories areused, a preservative such as methylparaben or propylparaben can beemployed.

Topical preparations containing the active drug component can be admixedwith a variety of carrier materials well known in the art, such as,e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eoils, mineral oil, PPG2 myristyl propionate, and the like, to form,e.g., alcoholic solutions, topical cleansers, cleansing creams, skingels, skin lotions, and shampoos in cream or gel formulations.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention can also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention can alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention can be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Formulations suitable for parenteral administration include formulationsthat comprise a sterile aqueous preparation of the active compound whichcan be isotonic with the blood of the recipient. Such formulationssuitably comprise a solution or suspension of a compound that isisotonic with the blood of the recipient subject. Such formulations cancontain distilled water, 5% dextrose in distilled water or saline andthe active compound. Often it is useful to employ a pharmaceutically andpharmacologically acceptable acid addition salt of the active compoundthat has appropriate solubility for the solvents employed. Usefulformulations also comprise concentrated solutions or solids comprisingthe active compound which on dilution with an appropriate solvent give asolution suitable for parenteral administration.

The compounds of the present invention can be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates, and cross-linked or amphipathic block copolymers ofhydrogels.

The pharmaceutical composition and method of the present invention canfurther comprise other therapeutically active compounds usually appliedin the treatment of the above mentioned conditions, includingosteoporosis, periodontal disease, bone fracture, bone damage followingbone reconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, post-menopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, hematopoietic disorders, such asfor example, aplastic anemia, pancreatic cancer, Alzheimer's disease,inflammatory arthritis, and joint repair.

For the treatment and prevention of osteoporosis, the compounds of thepresent invention can be administered in combination with abone-strengthening agent selected from antiresorptive agents,osteoanabolic agents, and other agents beneficial for the skeletonthrough mechanisms which are not precisely defined, such as calciumsupplements, flavonoids, and vitamin D analogs. The conditions ofperiodontal disease, bone fracture, and bone damage following bonereconstructive surgery can also benefit from these combined treatments.For example, the compounds of the instant invention can be effectivelyadministered in combination with effective amounts of other agents suchas estrogens, bisphosphonates, SERMs, cathepsin K inhibitors, αvβ3integrin receptor antagonists, vacuolar ATPase inhibitors, thepolypeptide osteoprotegerin, antagonists of VEGF, thiazolidinediones,calcitonin, protein kinase inhibitors, parathyroid hormone (PTH) andanalogs, calcium receptor antagonists, growth hormone secretagogues,growth hormone releasing hormone, insulin-like growth factor, bonemorphogenetic protein (BMP), inhibitors of BMP antagonism, prostaglandinderivatives, fibroblast growth factors, vitamin D and derivativesthereof, vitamin K and derivatives thereof, soy isoflavones, calciumsalts, and fluoride salts. The conditions of periodontal disease, bonefracture, and bone damage following bone reconstructive surgery can alsobenefit from these combined treatments.

In one embodiment of the present invention, a compound of the instantinvention can be effectively administered in combination with aneffective amount of at least one bone-strengthening agent chosen fromestrogen, and estrogen derivatives, alone or in combination withprogestin or progestin derivatives; bisphosphonates; antiestrogens orselective estrogen receptor modulators; αvβ3 integrin receptorantagonists; cathepsin K inhibitors; osteoclast vacuolar ATPaseinhibitors; calcitonin; and osteoprotegerin.

In the treatment of osteoporosis, the activity of the compounds of thepresent invention are distinct from that of the anti-resorptive agents:estrogens, bisphosphonates, SERMs, calcitonin, cathepsin K inhibitors,vacuolar ATPase inhibitors, agents interfering with theRANK/RANKL/Osteoprotegerin pathway, p38 inhibitors or any otherinhibitors of osteoclast generation or osteoclast activation. Ratherthan inhibiting bone resorption, the compounds of structural formula Iaid in the stimulation of bone formation, acting, for example, oncortical bone, which is responsible for a significant part of bonestrength. The thickening of cortical bone substantially contributes to areduction in fracture risk, especially fractures of the hip. Thecombination of the tissue-selective androgen receptor modulators ofstructural formula I with anti-resorptive agents such as for exampleestrogen, bisphosphonates, antiestrogens, SERMs, calcitonin, αvβ3integrin receptor antagonists, HMG-CoA reductase inhibitors, vacuolarATPase inhibitors, and cathepsin K inhibitors is particularly useful dueto the complementary effect of the bone anabolic and antiresorptiveactions.

Bone antiresportive agents are those agents which are known in the artto inhibit the resorption of bone and include, for example, estrogen andestrogen derivatives which include steroidal compounds having estrogenicactivity such as, for example, 17β-estradiol, estrone, conjugatedestrogen (PREMARIN®), equine estrogen, 17β-ethynyl estradiol, and thelike. The estrogen or estrogen derivative can be employed alone or incombination with a progestin or progestin derivative. Nonlimitingexamples of progestin derivatives are norethindrone andmedroxy-progesterone acetate.

Bisphosphonates are also bone anti-resorptive agents. Non-limitingexamples of bisphosphonate compounds which can also be employed incombination with a compound of structural formula I of the presentinvention include:

-   (a) alendronate (also known as alendronic acid,    4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, alendronate    sodium, alendronate monosodium trihydrate or    4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium    trihydrate. Alendronate is described in U.S. Pat. No. 4,922,007, to    Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to    Kieczykowski, issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer    et al., issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et    al., issued Jul. 15, 1997, all of which are incorporated by    reference herein in their entirety;-   (b) [(cycloheptylamino)-methylene]-bis-phosphonate (incadronate),    which is described in U.S. Pat. No. 4,970,335, to Isomura et al.,    issued Nov. 13, 1990, which is incorporated by reference herein in    its entirety,-   (c) (dichloromethylene)-bis-phosphonic acid (clodronic acid) and the    disodium salt (clodronate), which are described in Belgium Patent    672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of which are    incorporated by reference herein in their entirety;-   (d) [1-hydroxy-3-(1-pyrrolidinyl)-propylidene]-bis-phosphonate    (EB-1053);-   (e) (1-hydroxyethylidene)-bis-phosphonate (etidronate);-   (f) [1-hydroxy-3-(methylpentylamino)propylidene]-bis-phosphonate    (ibandronate), which is described in U.S. Pat. No. 4,927,814, issued    May 22, 1990, which is incorporated by reference herein in its    entirety;-   (g) (6-amino-)-1-hydroxyhexylidene)-bis-phosphonate (neridronate);-   (h) [3-(dimethylamino)-1-hydroxypropylidene]-bis-phosphonate    (olpadronate);-   (i) (3-amino-1-hydroxypropylidene)-bis-phosphonate (pamidronate);-   (j) [2-(2-pyridinyl)ethylidene]-bis-phosphonate (piridronate), which    is described in U.S. Pat. No. 4,761,406, which is incorporated by    reference in its entirety;-   (k) [1-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonate    (risedronate);-   (l) {[(4-chlorophenyl)thio]methylene}-bis-phosphonate (tiludronate),    which is described in U.S. Pat. No. 4,876,248, to Breliere et al.,    Oct. 24, 1989, which is incorporated by reference herein in its    entirety;-   (m) [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bis-phosphonate    (zoledronate); and-   (n)    [1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]-bis-phosphonate    (minodronate).

In one embodiment of the methods and compositions of the presentinvention, the bisphosphonate is selected from the group chosen fromalendronate, clodronate, etidronate, ibandronate, incadronate,minodronate, neridronate, olpadronate, pamidronate, piridronate,risedronate, tiludronate, zoledronate, pharmaceutically acceptable saltsof these bisphosphonates, and mixtures thereof. In one variant, thebisphosphonate is selected from alendronate, risedronate, zoledronate,ibandronate, tiludronate, and clodronate. In a subclass of this class,the bisphosphonate is alendronate, pharmaceutically acceptable salts andhydrates thereof, and mixtures thereof. A particular pharmaceuticallyacceptable salt of alendronate is alendronate monosodium.Pharmaceutically acceptable hydrates of alendronate monosodium includethe monohydrate and the trihydrate. A particular pharmaceuticallyacceptable salt of risedronate is risedronate monosodium.Pharmaceutically acceptable hydrates of risedronate monosodium includethe hemi-pentahydrate.

Still further, antiestrogenic compounds such as raloxifene (see, e.g.,U.S. Pat. No. 5,393,763), clomiphene, zuclomiphene, enclomiphene,nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25, U-11,555A, U-100A, andsalts thereof, and the like (see, e.g., U.S. Pat. Nos. 4,729,999 and4,894,373) can be employed in combination with a compound of structuralformula I in the methods and compositions of the present invention.These agents are also known as SERMs, or selective estrogen receptormodulators, agents known in the art to prevent bone loss by inhibitingbone resorption via pathways believed to be similar to those ofestrogens.

SERMs can be used in combination with the compounds of the Formula I tobeneficially treat bone disorders including osteoporosis. Such agentsinclude, for example, tamoxifen, raloxifene, lasofoxifene, toremifene,azorxifene, EM-800, EM-652, TSE 424, clomiphene, droloxifene, idoxifene,and levormeloxifene [Goldstein, et al., “A pharmacological review ofselective estrogen receptor modulators,” Human Reproduction Update, 6:212-224 (2000), and Lufkin, et al., “The role of selective estrogenreceptor modulators in the prevention and treatment of osteoporosis,”Rheumatic Disease Clinics of North America, 27: 163-185 (2001)]. SERMsare also discussed in “Targeting the Estrogen Receptor with SERMs,” Ann.Rep. Med. Chem. 36: 149-158 (2001).

αvβ3 Integrin receptor antagonists suppress bone resorption and can beemployed in combination with the tissue selective androgen receptormodulators of structural formula I for the treatment of bone disordersincluding osteoporosis. Peptidyl as well as peptidomimetic antagonistsof the αvβ3 integrin receptor have been described both in the scientificand patent literature. For example, reference is made to W. J. Hoekstraand B. L. Poulter, Curr. Med. Chem. 5: 195-204 (1998) and referencescited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO98/30542; WO 99/15506; WO 99/15507; WO 00/03973; EP 853084; EP 854140;EP 854145; U.S. Pat. Nos. 5,204,350; 5,217,994; 5,639,754; 5,741,796;5,780,426; 5,929,120; 5,952,341; 6,017,925; and 6,048,861.

Evidence of the ability of αvp3 integrin receptor antagonists to preventbone resorption in vitro and in vivo has been presented (see V. W.Engleman et al., “A Peptidomimetic Antagonist of the αvβ3 IntegrinInhibits Bone Resorption In Vitro and Prevents Osteoporosis In Vivo,” J.Clin. Invest. 99: 2284-2292 (1997); S. B. Rodan et al., “A High AffinityNon-Peptide αvβ3 Ligand Inhibits Osteoclast Activity In Vitro and InVivo,” J. Bone Miner. Res. 11: S289 (1996); J. F. Gourvest et al.,“Prevention of OVX-Induced Bone Loss With a Non-peptidic ligand of theαvβ3 Vitronectin Receptor,” Bone 23: S612 (1998); M. W. Lark et al., “AnOrally Active Vitronectin Receptor αvβ3 Antagonist Prevents BoneResorption In Vitro and In Vivo in the Ovariectomized Rat,” Bone 23:S219 (1998)). Other αvβ3 antagonists are described in R. M. Keenan etal., “Discovery of Potent Nonpeptide Vitronectin Receptor (αvβ3)Antagonists,” J. Med. Chem. 40: 2289-2292 (1997); R. M. Keenan et al.,“Benzimidazole Derivatives As Arginine Mimetics in 1,4-BenzodiazepineNonpeptide Vitronectin Receptor (αvβ3) Antagonists,” Bioorg. Med. Chem.Lett. 8: 3165-3170 (1998); and R. M. Keenan et al., “Discovery of anImidazopyridine-Containing 1,4-Benzodiazepine Nonpeptide VitronectinReceptor (αvβ3) Antagonist With Efficacy in a Restenosis Model,” Bioorg.Med. Chem. lett. 8: 3171-3176 (1998).

Still other benzazepine, benzodiazepine and benzocycloheptene αvβ3integrin receptor antagonists are described in the following patentpublications: WO 96/00574, WO 96/00730, WO 96/06087, WO 96/26190, WO97/24119, WO 97/24122, WO 97/24124, WO 98/14192, WO 98/15278, WO99/05107, WO 99/06049, WO 99/15170, WO 99/15178, WO 99/15506, and U.S.Pat. No. 6,159,964, and WO 97/34865. αvβ3 integrin receptor antagonistshaving dibenzocycloheptene, dibenzocycloheptane and dibenzoxazepinescaffolds have been described in WO 97/01540, WO 98/30542, WO 99/11626,WO 99/15508, WO 00/33838, U.S. Pat. Nos. 6,008,213, and 6,069,158.

Other osteoclast integrin receptor antagonists incorporating backboneconformational ring constraints have been described in the patentliterature. Published patent applications or issued patents disclosingantagonists having a phenyl constraint include WO 98/00395, WO 99/32457,WO 99/37621, WO 99/44994, WO 99/45927,WO 99/52872, WO 99/52879, WO99/52896, WO 00/06169, EP 0 820,988, EP 0 820,991, U.S. Pat. Nos.5,741,796; 5,773,644; 5,773,646; 5,843,906; 5,852,210; 5,929,120;5,952,381; 6,028,223; and 6,040,311. Published patent applications orissued patents disclosing antagonists having a monocyclic ringconstraint include WO 99/26945, WO 99/30709, WO 99/30713, WO 99/31099,WO 99/59992, WO 00/00486, WO 00/09503, EP 0 796,855, EP 0 928,790, EP 0928,793, U.S. Pat. Nos. 5,710,159; 5,723,480; 5,981,546; 6,017,926; and6,066,648. Published patent applications or issued patents disclosingantagonists having a bicyclic ring constraint include WO 98/23608, WO98/35949, WO 99/33798, EP 0 853,084, U.S. Pat. Nos. 5,760,028;5,919,792; and 5,925,655.

Reference is also made to the following reviews for additionalscientific and patent literature that concern alpha v integrinantagonists: M. E. Duggan, et al., “Ligands to the integrin receptorα_(v)β₃ , Exp. Opin. Ther. Patents, 10: 1367-1383 (2000); M. Gowen, etal., “Emerging therapies for osteoporosis,” Emerging Drugs, 5: 1-43(2000); J. S. Kerr, et al., “Small molecule α_(v) integrin antagonists:novel anticancer agents,” Exp. Opin. Invest. Drugs, 9: 1271-1291 (2000);and W. H. Miller, et al., “Identification and in vivo efficacy ofsmall-molecule antagonists of integrin α_(v)β₃ (the vitronectinreceptor),” Drug Discovery Today, 5: 397-408 (2000).

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.Non-limiting examples of cathespin K inhibitors can be found in PCTInternational Publications assigned to Merck Frost Canada and AxixPharmaceuticals: WO 01/49288, published Jul. 7, 2001, and WO 01/77073,published Oct. 18, 2001.

Members of the class of HMG-CoA reductase inhibitors, known as the“statins,” have been found to trigger the growth of new bone, replacingbone mass lost as a result of osteoporosis (see The Wall Street Journal,Friday, Dec. 3, 1999, page B1). Therefore, the statins hold promise forthe treatment of bone resorption. Examples of HMG-CoA reductaseinhibitors include statins in their lactonized or dihydroxy open acidforms and pharmaceutically acceptable salts and esters thereof,including but not limited to lovastatin (see U.S. Pat. No. 4,342,767);simvastatin (see U.S. Pat. No. 4,444,784); dihydroxy open-acidsimvastatin, particularly the ammonium or calcium salts thereof;pravastatin, particularly the sodium salt thereof (see U.S. Pat. No.4,346,227); fluvastatin, particularly the sodium salt thereof (see U.S.Pat. No. 5,354,772); atorvastatin, particularly the calcium salt thereof(see U.S. Pat. No. 5,273,995); cerivastatin, particularly the sodiumsalt thereof (see U.S. Pat. No. 5,177,080), rosuvastatin, also known asZD-4522 (see U.S. Pat. No. 5,260,440) and pitavastatin, also referred toas NK-104, itavastatin, or nisvastatin (see PCT internationalapplication publication number WO 97/23200).

Osteoclast vacuolar ATPase inhibitors, also called proton pumpinhibitors, can also be employed together with the tissue selectiveandrogen receptor modulators of structural formula I. The proton ATPasewhich is found on the apical membrane of the osteoclast has beenreported to play a significant role in the bone resorption process.Therefore, this proton pump represents an attractive target for thedesign of inhibitors of bone resorption which are potentially useful forthe treatment and prevention of osteoporosis and related metabolicdiseases [see C. Farina et al., “Selective inhibitors of the osteoclastvacuolar proton ATPase as novel bone antiresorptive agents,” DDT, 4:163-172 (1999)].

The angiogenic factor VEGF has been shown to stimulate thebone-resorbing activity of isolated mature rabbit osteoclasts viabinding to its receptors on osteoclasts [see M. Nakagawa et al.,“Vascular endothelial growth factor (VEGF) directly enhancesosteoclastic bone resorption and survival of mature osteoclasts,” FEBSLetters, 473: 161-164 (2000)]. Therefore, the development of antagonistsof VEGF binding to osteoclast receptors, such as KDR/Flk-1 and Flt-1,can provide yet a further approach to the treatment or prevention ofbone resorption.

Activators of the peroxisome proliferator-activated receptor-γ (PPARγ),such as the thiazolidinediones (TZD's), inhibit osteoclast-like cellformation and bone resorption in vitro. Results reported by R. Okazakiet al. in Endocrinology, 140: 5060-5065 (1999) point to a localmechanism on bone marrow cells as well as a systemic one on glucosemetabolism. Nonlimiting examples of PPARγ, activators include theglitazones, such as troglitazone, pioglitazone, rosiglitazone, and BRL49653.

Calcitonin can also be employed together with the tissue selectiveandrogen receptor modulator of structural formula I. Calcitonin ispreferentially employed as salmon nasal spray (Azra et al., Calcitonin.1996. In: J. P. Bilezikian, et al., Ed., Principles of Bone Biology, SanDiego: Academic Press; and Silverman, “Calcitonin,” Rheumatic DiseaseClinics of North America, 27: 187-196, 2001)

Protein kinase inhibitors can also be employed together with the tissueselective androgen receptor modulators of structural formula I. Kinaseinhibitors include those disclosed in WO 01/17562 and are in oneembodiment selected from inhibitors of p38. Non-limiting examples of p38inhibitors useful in the present invention include SB 203580 [Badger etal., “Pharmacological profile of SB 203580, a selective inhibitor ofcytokine suppressive binding protein/p38 kinase, in animal models ofarthritis, bone resorption, endotoxin shock, and immune function,” J.Pharmacol. Exp. Ther., 279: 1453-1461 (1996)].

Osteoanabolic agents are those agents that are known to build bone byincreasing the production of the bone protein matrix. Such osteoanabolicagents include, for example, the various forms of parathyroid hormone(PTH) such as naturally occurring PTH (1-84), PTH (1-34), analogsthereof, native or with substitutions and particularly parathyroidhormone subcutaneous injection. PTH has been found to increase theactivity of osteoblasts, the cells that form bone, thereby promoting thesynthesis of new bone (Modern Drug Discovery, Vol. 3, No. 8, 2000). Aninjectable recombinant form of human PTH, Forteo (teriparatide), hasreceived regulatory approval in the U.S. for the treatment ofosteoporosis. Thus, PTH and fragments thereof, such as hPTH(1-34), canprove to be efficacious in the treatment of osteoporosis alone or incombination with other agents, such as the tissue selective androgenreceptor modulators of the present invention.

Also useful in combination with the SARMs of the present invention arecalcium receptor antagonists which induce the secretion of PTH asdescribed by Gowen et al., in “Antagonizing the parathyroid calciumreceptor stimulates parathyroid hormone secretion and bone formation inosteopenic rats,” J. Clin. Invest. 105: 1595-604 (2000).

Additional osteoanabolic agents include growth hormone secretagogues,growth hormone, growth hormone releasing hormone and the like are can beemployed with the compounds according to structural formula I for thetreatment of osteoporosis. Representative growth hormone secretagoguesare disclosed in U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,006,979; U.S.Pat. No. 4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,283,241;U.S. Pat. No. 5,284,841; U.S. Pat. No. 5,310,737; U.S. Pat. No.5,317,017; U.S. Pat. No. 5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat.No. 5,434,261; U.S. Pat. No. 5,439.136; U.S. Pat. No. 5,494,919; U.S.Pat. No. 5,494,920; U.S. Pat. No. 5,492,916; U.S. Pat. No. 5,536,716;EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT PatentPub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub.No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO95/34311; PCT Patent Pub. No. WO 96/02530; Science 260, 1640-1643 (Jun.11, 1993); Ann. Rep. Med. Chem., 28: 177-186 (1993); Bioorg. Med. Chem.Lett., 4: 2709-2714(1994); and Proc. Natl. Acad. Sci. USA. 92: 7001-7005(1995).

Insulin-like growth factor (IGF) can also be employed together with thetissue selective androgen receptor modulators of structural formula I.Insulin-like growth factors can be selected from Insulin-like GrowthFactor I, alone or in combination with IGF binding protein 3 and IGF II[See Johannson and Rosen, “The IGFs as potential therapy for metabolicbone diseases,” 1996, In: Bilezikian, et al., Ed., Principles of BoneBiology, San Diego: Academic Press; and Ghiron et al., “Effects ofrecombinant insulin-like growth factor-I and growth hormone on boneturnover in elderly women,” J. Bone Miner. Res. 10: 1844-1852(1995)].

Bone morphogenetic protein (BMP) can also be employed together with thetissue selective androgen receptor modulators of structural formula I.Bone morphogenetic protein includes BMP 2, 3, 5, 6, 7, as well asrelated molecules TGF beta and GDF 5 [Rosen et al., “Bone morphogeneticproteins,” 1996. In: J. P. Bilezikian, et al., Ed., Principles of BoneBiology, San Diego: Academic Press; and Wang E A, “Bone morphogeneticproteins (BMPs): therapeutic potential in healing bony defects,” TrendsBiotechnol., 11: 379-383 (1993)].

Inhibitors of BMP antagonism can also be employed together with thetissue selective androgen receptor modulators of structural formula I.In one embodiment, BMP antagonist inhibitors are chosen from inhibitorsof the BMP antagonists SOST, noggin, chordin, gremlin, and dan [Massagueand Chen, “Controlling TGF-beta signaling,” Genes Dev., 14:627-644,2000; Aspenberg et al., “The bone morphogenetic proteinsantagonist Noggin inhibits membranous ossification,” J. Bone Miner. Res.16: 497-500, 2001; Brunkow et al., “Bone dysplasia sclerosteosis resultsfrom loss of the SOST gene product, a novel cystine knot-containingprotein,” Am. J. Hum. Genet. 68: 577-89 (2001)].

The tissue-selective androgen receptor modulators of the presentinvention can also be combined with the polypeptide osteoprotegerin forthe treatment of conditions associated with bone loss, such asosteoporosis. The osteoprotegerin can be selected from mammalianosteoprotegerin and human osteoprotegerin. The polypeptideosteoprotegerin, a member to the tumor necrosis factor receptorsuperfamily, is useful to treat bone diseases characterized by increasedbone loss, such as osteoporosis. Reference is made to U.S. Pat. No.6,288,032, which is incorporated by reference herein in its entirety.

Prostaglandin derivatives can also be employed together with the tissueselective androgen receptor modulators of structural formula I.Non-limiting representatives of prostaglandin derivatives are selectedfrom agonists of prostaglandin receptors EP1, EP2, EP4, FP, IP andderivatives thereof [Pilbeam et al., “Prostaglandins and bonemetabolism,” 1996. In: Bilezikian, et al. Ed. Principles of BoneBiology, San Diego: Academic Press; Weinreb et al., “Expression of theprostaglandin E(2) (PGE(2)) receptor subtype EP(4) and its regulation byPGE(2) in osteoblastic cell lines and adult rat bone tissue,” Bone, 28:275-281 (2001)].

Fibroblast growth factors can also be employed together with the tissueselective androgen receptor modulators of structural formula I.Fibroblast growth factors include aFGF, bFGF and related peptides withFGF activity [Hurley Florkiewicz, “Fibroblast growth factor and vascularendothelial growth factor families,” 1996. In: J. P. Bilezikian, et al.,Ed. Principles of Bone Biology, San Diego: Academic Press].

In addition to bone resorption inhibitors and osteoanabolic agents,there are also other agents known to be beneficial for the skeletonthrough mechanisms which are not precisely defined. These agents canalso be favorably combined with the tissue selective androgen receptormodulators of structural formula I.

Vitamin D and vitamin D derivatives can also be employed together withthe tissue selective androgen receptor modulator of structural formulaI. Vitamin D and vitamin D derivatives include, for example, naturalvitamin D, 25-OH-vitamin D3, 1α,25(OH)₂ vitamin D3, 1α-OH-vitamin D3,1α-OH-vitamin D2, dihydrotachysterol, 26,27-F6-1α,25(OH)₂ vitamin D3,19-nor-1α,25(OH)₂ vitamin D3, 22-oxacalcitriol, calcipotriol,1α,25(OH)₂-16-ene-23-yne-vitamin D3 (Ro 23-7553), EB1089,20-epi-1α,25(OH)₂ vitamin D3, KH1060, ED71, 1α,24(S)—(OH)₂ vitamin D3,1α,24(R)—(OH)2 vitamin D3 [See, Jones G., “Pharmacological mechanisms oftherapeutics: vitamin D and analogs,” 1996. In: J. P. Bilezikian, et.al. Ed. Principles of Bone Biology, San Diego: Academic Press].

Vitamin K and vitamin K derivatives can also be employed together withthe tissue selective androgen receptor modulators of structural formulaI. Vitamin K and vitamin K derivatives include menatetrenone (vitaminK2) [see Shiraki et al., “Vitamin K2 (menatetrenone) effectivelyprevents fractures and sustains lumbar bone mineral density inosteoporosis,” J. Bone Miner. Res., 15: 515-521(2000)].

Soy isoflavones, including ipriflavone, can be employed together withthe tissue selective androgen receptor modulators of structural formulaI.

Fluoride salts, including sodium fluoride (NaF) and monosodiumfluorophosphate can also be employed together with the tissue selectiveandrogen receptor modulators of structural formula I. Dietary calciumsupplements can also be employed together with the tissue selectiveandrogen receptor modulators of structural formula I. Dietary calciumsupplements include calcium carbonate, calcium citrate, and naturalcalcium salts (Heaney. Calcium. 1996. In: J. P. Bilezikian, et al., Ed.,Principles of Bone Biology, San Diego: Academic Press).

Daily dosage ranges for bone resorption inhibitors, osteoanabolic agentsand other agents which can be used to benefit the skeleton when used incombination with a compound of structural formula I are those which areknown in the art. In such combinations, generally the daily dosage rangefor the tissue selective androgen receptor modulator of structuralformula I is 0.01 to 1000 mg per adult human per day, such as forexample, from 0.1 to 200 mg/day. However, adjustments to decrease thedose of each agent can be made due to the increased efficacy of thecombined agent.

In particular, when a bisphosphonate is employed, dosages of 2.5 to 100mg/day (measured as the free bisphosphonic acid) are appropriate fortreatment, such as for example ranging from 5 to 20 mg/day, or about 10mg/day. Prophylactically, doses of about 2.5 to about 10 mg/day andespecially about 5 mg/day should be employed. For reduction inside-effects, it can be desirable to administer the combination of acompound of structural formula I and the bisphosphonate once a week. Foronce weekly administration, doses of about 15 mg to 700 mg per week ofbisphosphonate and 0.07 to 7000 mg of a compound of structural formula Ican be employed, either separately, or in a combined dosage form. Acompound of structural formula I can be favorably administered in acontrolled-release delivery device, particularly for once weeklyadministration.

For the treatment of atherosclerosis, hypercholesterolemia, andhyperlipidemia, the compounds of structural formula I can be effectivelyadministered in combination with one or more additional active agents.The additional active agent or agents can be chosen from lipid-alteringcompounds such as HMG-CoA reductase inhibitors, agents having otherpharmaceutical activities, and agents that have both lipid-alteringeffects and other pharmaceutical activities. Non-limiting examples ofHMG-CoA reductase inhibitors include statins in their lactonized ordihydroxy open acid forms and pharmaceutically acceptable salts andesters thereof, including but not limited to lovastatin (see U.S. Pat.No. 4,342,767); simvastatin (see U.S. Pat. No. 4,444,784); dihydroxyopen-acid simvastatin, particularly the ammonium or calcium saltsthereof; pravastatin, particularly the sodium salt thereof (see U.S.Pat. No. 4,346,227); fluvastatin, particularly the sodium salt thereof(see U.S. Pat. No. 5,354,772); atorvastatin, particularly the calciumsalt thereof (see U.S. Pat. No. 5,273,995); cerivastatin, particularlythe sodium salt thereof (see U.S. Pat. No. 5,177,080), and nisvastatin,also referred to as NK-104 (see PCr international applicationpublication number WO 97/23200).

Additional active agents which can be employed in combination with acompound of structural formula I include, but are not limited to,HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; cholesterol absorption inhibitors, such asSCH-58235, also known as ezetimibe and1-(4-fluorophenyl)-3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl)]4(S)-(4-hydroxyphenyl)2-azetidinone,which is described in U.S. Pat. Nos. 5,767,115 and 5,846,966; bile acidsequestrants; LDL (low density lipoprotein) receptor inducers; plateletaggregation inhibitors, for example glycoprotein Ilb/iIa fibrinogenreceptor antagonists and aspirin; human peroxisome proliferatoractivated receptor gamma (PPARγ), agonists, including the compoundscommonly referred to as glitazones, for example troglitazone,pioglitazone and rosiglitazone and, including those compounds includedwithin the structural class known as thiazolidinediones as well as thosePPARγ, agonists outside the thiazolidinedione structural class; PPARαagonists, such as clofibrate, fenofibrate including micronizedfenofibrate, and gemfibrozil; PPAR dual α/γ agonists; vitamin B₆ (alsoknown as pyridoxine) and the pharmaceutically acceptable salts thereofsuch as the HCl salt; vitamin B₁₂ (also known as cyanocobalamin); folicacid or a pharmaceutically acceptable salt or ester thereof such as thesodium salt and the methylglucamine salt; anti-oxidant vitamins such asvitamin C and E and beta carotene; beta-blockers; angiotensin IIantagonists such as losartan; angiotensin converting enzyme inhibitors,such as enalapril and captopril; calcium channel blockers, such asnifedipine and diltiazem; endothelin antagonists; agents such as LXRligands that enhance ABC1 gene expression; bisphosphonate compounds,such as alendronate sodium; and cyclooxygenase-2 inhibitors, such asrofecoxib and celecoxib, as well as other agents known to be useful inthe treatment of these conditions.

Daily dosage ranges for IMG-CoA reductase inhibitors when used incombination with the compounds of structural formula I correspond tothose which are known in the art. Similarly, daily dosage ranges for theHMG-COA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MT) inhibitors;probucol; niacin; cholesterol absorption inhibitors including ezetimibe;bile acid sequestrants; LDL (low density lipoprotein) receptor inducers;platelet aggregation inhibitors, including glycoprotein IIb/IIIafibrinogen receptor antagonists and aspirin; human peroxisomeproliferator activated receptor gamma (PPARγ) agonists; PPARα agonists;PPAR dual α/γ agonists; vitamin B₆; vitamin B₁₂; folic acid;anti-oxidant vitamins; beta-blockers; angiotensin II antagonists;angiotensin converting enzyme inhibitors; calcium channel blockers;endothelin antagonists; agents such as LXR ligands that enhance ABC1gene expression; bisphosphonate compounds; and cyclooxygenase-2inhibitors also correspond to those which are known in the art, althoughdue to the combined action with the compounds of structural formula I,the dosage can be somewhat lower when administered in combination.

One embodiment of the invention is a method for effecting a boneturnover marker in a mammal comprising administering a therapeuticallyeffective amount of a compound according to formula I. Non-limitingexamples of bone turnover markers can be selected from urinaryC-telopeptide degradation products of type I collagen (CTX), urinaryN-telopeptide cross-links of type I collagen (NTX), DXA, and DPD.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment and the term “administering” is to be interpreted accordingly.It will be understood that the scope of combinations of the compounds ofthis invention with other agents useful for treating diseases caused byandrogen deficiency or that can be ameliorated by addition of androgen.

Abbreviations Used in the Description of the Preparation of theCompounds of the Present Invention:

AcOH Acetic acid Bcz-Cl Benzylchloride BOC(Boc): t-Butyloxycarbonyl.calc. Calculated CDI Carbonyl-1,1′-diimidazole DHT dihydrotestosteroneDIPEA Diisopropylethylamine DMSO Dimethyl sulfoxide DMFN,N-Dimethylformamide EA Ethyl acetate EDTA Ethylenediaminetetraaceticacid EtOH Ethanol H¹NMR Proton Nuclear Magnetic Resonance HPLCHigh-performance liquid chromatography Hunig's baseDiisopropylethylamine LCMS Liquid chromotography/mass spectroscopy MeOHMethonol Py-Bop Benzotriazole-1-yl-oxy-trispyrrolidinophosphoniumhexafluorophosphate rt Room temperature TFA Trifluoracetic acid TLCThin-layer chromatography {circle around (P)} Protecting Group* *Thecircled “P” as used herein signifies any suitable protecting group forthe nitrogen or oxygen to which it is attached. The identity of suitableprotecting groups would be readily known to those of ordinary skill inthe art. The reaction conditions to carry out the protection anddeprotection are also well known in the literature. Further informationregarding suitable protecting groups may be found in Protective Groupsin Organic Chemistry by Peter G. Wuts and Theodora W. Greene, John Wiley& Sons, 3^(rd) ed. (1999).

EXAMPLES

The compounds of the present invention can be prepared according to theprocedures denoted in the following reaction Schemes and Examples ormodifications thereof using readily available starting materials,reagents, and conventional procedures or variations thereof well-knownto a practitioner of ordinary skill in the art of synthetic organicchemistry. Specific definitions of variables in the Schemes are givenfor illustrative purposes only and are not intended to limit theprocedures described.

The following examples are provided to further illustrate details forthe preparation and use of the compounds of the present invention. Theyare not intended to be limitations on the scope of the instant inventionin any way, and they should not be so construed. Furthermore, thecompounds described in the following examples are not to be construed asforming the only genus that is considered as the invention, and anycombination of the compounds or their moieties can itself form a genus.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are in degreesCelsius unless noted otherwise.

The selective androgen receptor modulators (SARMs) of formula I wereprepared as outlined in Schemes A, B, and C.

General Schemes

Example 1 (4-Amino-3-nitro-phenyl)-carbamic acid tert-butyl ester (1-3)

A solution of 2-nitro-benzene-1,4-diamine (1-1, 1.01 g, 6.53 mol) intert-butanol (20 mL) was treated with di-tert-butyl dicarbonate (1.42 g,6.53 mol) and heated at 40C. After 1 h stirring at the same temperature,the reaction mixture was cooled to the ambient temperature andconcentrated in vacuo. The resulting crude mixture was dissolved inethyl acetate, treated with active carbon, and filtered though a pad ofCelite (3 g). The filtrate solution was concentrated in vacuo to affordthe desired product as a deep orange powder. The intermediate (1-2) wasdissolved in methanol (20 mL) and mixed with palladium on carbon (10%,50 mg). Hydrogen gas was bubbled into the reaction mixture at theambient temperature for 1 h. Any insoluble material was removed byfiltration and the filtrate solution was concentrated in vacuo. Theresulting crude product was triturated with ethyl acetate (10 mL) andhexanes (2 mL) to give (4-Amino-3-nitro-phenyl)-carbamic acid tert-butylester (1-3) as a pale gray solid. The product was stored at −15° C. in abrown bottle; ¹H NMR (500 MHz, DMSO-d₆) δ 8.82 (s, 1H), 6.84 (s, 1H),6.56 (d, 1H, J=8.5 Hz), 6.49 (d, 1H, J=8.0 Hz), 5.71 (bs, 4H).

Example 2 2-Thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-5)

A solution of (4-Amino-3-nitro-phenyl)-carbamic acid tert-butyl ester(1-3, 0.409 g, 1.832 mmol), thiazole 4-carboxylic acid (0.226 g, 1.832mmol) and diisopropylethylamine (0.81 mL, 4.03 mmol) inN,N-dimethylformamide (10 mL) was reacted at the ambient temperaturewith benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate(PyBop, 1.05 g, 2.02 mmmol). After 3 h stirring at the same temperature,the reaction mixture was concentrated under the reduced pressure and theresidue was partitioned between ethyl acetate (100 mL) and aqueous0.5N-NaOH solution (70 mL). The organic layer was washed with brine,separated, dried (MgSO₄) and concentrated in vacuo. The resulting crudeproduct was triturated with ethyl acetate (5 mL), collected byfiltration, and dried under the reduced pressure. The mixture of theintermediate products (1-4a and 1-4b) was dissolved in aqueous20%(v/v)-acetic acid (50 mL) and heated at reflux for 2 h. The reactionmixture was cooled to the ambient temperature and concentrated in vacuo.The resulting crude thick oil was partitioned between ethyl acetate (100mL) and saturated aqueous sodium bicarbonate solution (70 mL). Theorganic layer was washed with brine, separated, dried (MgSO₄) andconcentrated in vacuo. The crude product was triturated with ethylacetate (15 mL) and hexanes (2 mL). The resulting solid,2-thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-5), was collected byfiltration and dried under the reduced pressure; ¹H NMR (500 MHz,DMSO-d₆) δ 12.34 (s, 1H), 9.27 (s, 1H), 8.24 (s, 1H), 7.27 (bs, 1H),6.66 (s, 1H), 6.54 (d, 1H, J=7.5 Hz), 4.96 (bs, 2H).

Compounds 1-6 through 1-9 in Table 1 below can be prepared fromcommercially available materials as described in Examples 1 and 2.Alternatively, arylaldehydes can react with 1-3 to form thecorresponding benzimidazoles as disclosed by Jonas, R.; Klockow, M.;Lues, I.; Pruecher, H.; Schliep, H. J.; Wurziger, H.; Eur. J. Med. Chem.1993, 28, 129.

TABLE 1 # Structure Nomenclature 1-6

2-Pyridin-2-yl-3H-benzoimidazol-5-ylamine; HRMS = 211.0907 1-7

2-Oxazol4-yl-3H-benzoimidazol-5-ylamine; HRMS = 201.0671 1-8

2-(1H-Pyrazol-3-yl)-3H-benzoimidazol-5-ylamine; HRMS = 200.0852 1-9

2-(1-Methyl-1H-pyrazol-3-yl)-3H-benzoimidazol-5- ylamine; HRMS =214.1022

Example 31-[2-(3-Fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea(2-77)

A solution of 2-thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-5, 100 mg,0.46 mmol) in N,N-dimethylformamide (2 mL). The 1,1′-carbonyldiimidazole(CDI, 82 mg, 0.51 mmol) was added in one sum to the solution and wasstirred for two hours. The 3-fluorophenethylamine (2-1, 72 uL, 0.56mmol) was added to the reaction mixture via pipet and stirred tocompletion by LCMS analysis. The LCMS indicated that the dibenzimidazoleurea was the by-product. The reaction mixture was partitioned betweenethyl acetate and dilute sodium bicarbonate solution. The insoluble ureaby-product was removed by vacuum filtration of the layers and theaqueous was extracted (3×10 mL) with ethyl acetate. The organic layerwas washed twice with water, once with brine, separated, dried (Na₂SO₄),filtered, and concentrated in vacuo. The resulting red solid wastriturated in ethyl acetate/hexanes mixtures to afford the pure1-[2-(3-fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-ureaas a gray solid (2-77); ¹H NMR (500 MHz, DMSO-d₆) δ 12.72 (s, 1H), 9.31(t, 1H, J=2.0 Hz), 8.52 (s, 1H), 8.34 (d, 1H, J=2.0 Hz), 7.87 (d, 1H,J=1.0 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.35 (d, 1H, J=6.5 Hz), 7.11 (d, 2H,J=8.0 Hz), 7.04 (dt, 1H, J=8.5, 2.0 Hz), 6.96 (dd, 1H, J=8.5, 2.0 Hz),6.06 (m, 1H), 3.38 (q, 2H, J=7.0 Hz), 2.80 (t, 2H, J=7.0 Hz).

Example 46-({[(3,5-Difluorophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benziniidazol-1-iumtrifluoroacetate (2-26)

A solution of 2-thiazolyl-3H-benzoimidazol-5-ylamine (1-5, 600 uL, 0.231mmol) of in DMF (0.385M) was added to a 4 dram reaction vial with ateflon cap. The isocyanate (2-2, 43 mg, 0.277 mmols) was added to theamine solution and the vial was rotated overnight to completion. Themixture was treated with trisamine resin to scavenge remainingisocyanate and rotated for 2 hrs prior to being filtered into a testtube (13×100). The crude urea was purified by mass-guided reverse-phasechromatography as the mono-TFA salt; HRMS (M+H)=372.0747.

Compounds 2-3 through 2-77 in Table 2 below were prepared, as shown inExamples 3 and 4, from commercially available amines or isocyanates.Selected spectra are as follow: 2-3, ¹H NMR (500 MHz, DMSO-d₆) δ 12.77(s, 1H), 9.31 (t, 1H, J=2.0 Hz), 8.35 (d, 1H, J=3.0 Hz), 7.69 (s, 1H),7.53-7.39 (m, 3H), 7.28 (m, 2H), 7.17 (s, 1H), 7.05 (s, 1H), 6.99 (dd,1H, J=8.5, 2.0 Hz), 4.72 (m, 1H), 1.05 (d, 6H, J=11.0 Hz); 2-4, ¹H NMR(500 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.30 (app t, 1H, J=2.5 Hz), 8.45 (s,1H), 8.33 (d, 1H, J=1.5 Hz), 7.84 (d, 1H, J=2.0 Hz), 7.47 (d, 1H, J=8.5Hz), 7.33 (m, 4H), 7.24 (t, 1H, J=6.5 Hz), 6.93 (dd, 1H, J=8.5, 2.0 Hz),6.57 (m, 1H), 4.63 (m, 1H), 1.73 (m, 2H), 0.86 (t, 3H, J=7.0 Hz); 2-5,¹H NMR (500 Mz, DMSO-d₆) δ 12.74 (s, 1H), 9.31 (s, 1H), 8.76 (s, 1H),8.34 (d, 1H, J=1.0 Hz), 7.86 (s, 1H), 7.49 (m, 2H), 7.37 (s, 2H), 7.02(d, 1H, J=8.5 Hz), 6.71 (m, 1H), 4.32 (d, 2H, J=5.5 Hz).

TABLE 2 # Structure Nomenclature & HRMS (M + 1) 2-3

N-isopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 378.1378 2-4

N-[(1R)-1-phenylpropyl]-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 378.1378 2-5

N-(3,5-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 418.0294 2-6

N-benzyl-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea; HRMS =350.1068 2-7

N-butyl-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol- 5-yl]urea; HRMS =316.1228 2-8

N-(2-phenylethyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 364.1226 2-9

N-(2-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 364.122 2-10

N-(2-fluorobenzyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 368.0977 2-11

N-(2-chlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 384.067 2-12

N-[(1S)-1-phenylethyl]-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 364.1227 2-13

N-(3-fluorobenzyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 368.0977 2-14

N-(4-methylbenzyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 364.1225 2-15

N-(4-fluorobenzyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 368.0978 2-16

N-(2,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 418.0277 2-17

N-(3,4-dichlorobenzyl)-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 418.0277 2-18

N-(4-methoxyphenyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 366.1012 2-19

N-(3-methylbenzyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-6-yl]urea;HRMS = 364.1226 2-20

N-(2-phenylcyclopropyl)-N′-[-2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea; HRMS = 376.1241 2-21

N-(4-bromobenzyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-6-yl]urea;HRMS = 428.0164 2-22

N-(4-methoxybenzyl)-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-6-yl]urea;HRMS = 380.1174 2-23

6-({[(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-1H-benzimidazol-1-ium trifluoroacetate; HRMS =350.1072 2-24

6-[({[(1R)-1-phenylethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =364.1222 2-25

6-[({[1-(1-naphthyl)ethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =414.1388 2-26

6-({[(3,5-difluorophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =372.0747 2-27

N-methyl-N-phenyl-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 350.4212 2-28

N-benzyl-N-methyl-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-6-yl]urea;HRMS = 364.4423 2-29

N-[-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide; HRMS = 376.4638 2-30

N-(2-(1,3-thiazol-4-yl)-1H-benzirnidazol-6-yl]-3,4-dihydroquinoline-1(2H)-carboxamide; HRMS = 376.4638 2-31

N-ethyl-N-phenyl-N′-[-(1,3-thiazol-4-yl)-1H- benzimidazol-5-yl]urea;HRMS = 364.1224 2-32

6-({[methyl(2- methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS = 364.12122-33

6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 364.1212 2-34

6-({[methyl(4-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 364.1218 2-35

N-(4-hydroxyphenyl)-N-methyl-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 366.1 2-36

6-({[sec-butyl(phenyl)amino]carbonyl}amino)-1-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =392.1538 2-37

6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS = 376.12192-38

6-({[(2-hydroxyethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 380.1171 2-39

6-({[(4-hydroxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 366.1 2-40

N-(2-chlorophenyl)-N-methyl-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 384.0617 2-41

6-({[3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 384.0686 2-42

6-({[(4-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 384.0675 2-43

6-({[(2-cyanoethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 389.1168 2-44

6-[({methyl[4-(trifluoromethoxy)phenyl]-amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 434.0874 2-45

6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 418.0288 2-46

6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 386.0879 2-47

6-({[benzyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =426.1386 2-48

6-({[methyl(1-naphthyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =400.1227 2-49

6-({[phenyl(1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 440.1472 2-50

6-({[cyclohexyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =418.1697 2-51

N-(1-phenylcyclopropyl)-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea; HRMS = 376.46 2-52

N-(4-chlorophenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 384.0675 2-53

6-({[(1-methyl-1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 378.1403 2-54

6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1- ium trifluoroacetate;HRMS = 378.1398 2-55

6-[({[(1S)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1- ium trifluoroacetate;HRMS = 378.1398 2-56

6-({[(3-chlorobenzyl)amnino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =384.0687 2-57

6-({[(2,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =418.0291 2-58

6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =418.0294 2-59

2-(1,3-thiazol-4-yl)-6-[({[3-(trifluoromethyl)benzyl]amino}carbonyl)amino]- 3H-benzimidazol-1-iumtrifluoroacetate; HRMS = 418.0948 2-60

6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS = 378.13942-61

6-[({methyl[(1R)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1- ium trifluoroacetate;HRMS = 378.1394 2-62

6-[({methyl[(1S)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1- ium trifluoroacetate;HRMS = 378.1395 2-63

6-{[(2-phenylpyrrolidin-1-yl)carbonyl]amino }-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =390.1395 2-64

6-({[(2-phenylcyclopropyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 376.1241 2-65

6-({[(4-methoxyphenyl)(methyl)amino]-carbonyl)amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 380.119 2-66

6-({[(3,5- dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =378.1382 2-67

6-({[(5-isopropyl-2- methylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS =406.1712 2-68

6-({[(6-methoxypyridinium-2-yl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumbis(trifluoroacetate); HRMS = 381.114 2-69

6-({[ethyl(3- methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS = 392.15492-70

6-({[(3,4-dichlorobenzyl)(methyl)amino]-carbonyl)amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 432.0461 2-71

6-[({[(2-bromothien-3- yl)methyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate; HRMS = 433.9748 2-72

6-[({methyl[5-(trifluoromethyl)-1,3,4-thiadiazol-3-ium-2-yl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium bis(trifluoroacetate); HRMS = 426.0411 2-73

6-({[(2,4-dichlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H- benzimidazol-1-iumtrifluoroacetate; HRMS = 418.0298 2-74

N-cyclopropyl-N-phenyl-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea; HRMS = 376.46 2-75

N-[4-(hydroxymethyl)phenyl]-N-methyl-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea; HRMS = 380.1169 2-76

N-methyl-N′-[-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]-N-[-(trifluoromethoxy)- phenyl]urea; HRMS = 434.08792-77

1-[-(3-Fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea; HRMS = 382.116

Example 51-Phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide(3-10)

A solution of 1-phenylcyclopropane-1-carboxylic acid (2.0 g, 12.3 mmol)in dichloromethane (40 mL) was treated at ambient temperature withoxalyl chloride (1.06 mL, 12.3 mmol) and three drops of DMF. A dryingtube was placed on the flask and the reaction bubbled (HCl, CO, and CO₂)for three hours. 2-Thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-6, 2.67 g,12.3 mmol) and diisopropyl ethyl amine (3.22 mL, 18.5 mmol) weredissolved in 30 mL of dry N,N-dimethylformamide and cooled to 0° C. Theacid chloride solution was concentrated, re-dissolved in 10 mL ofdichloromethane, and cannulated into the stirring amine solution over afive minute period. The reaction was allowed to warm slowly to ambienttemperature after the addition was complete. The reaction was completeafter half an hour by TLC analysis and was partitioned between ethylacetate and dilute sodium bicarbonate solution. The aqueous wasextracted (3×10 mL) with ethyl acetate and the layers were separated.The organic layer was washed twice with water, once with brine,separated, dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting yellow oil was filtered thru a plug of silica gel eluted withethyl acetate. The filtrate was concentrated in vacuo and the residuewas triturated in ethyl acetate/hexanes mixtures to afford the pure1-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamideas a white solid (3-10); ¹H NMR (500 MHz, DMSO-d₆) δ 12.87 (s, 1H), 9.31(s, 1H), 9.10 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.49 (d, 1H), 7.36(m, 6H), 1.48 (dd, 2H, J=4.4, 2.4 Hz), 1.15 (dd, 2H, J=4.4, 2.4 Hz).

Example 6(2S)-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]propanamide(3-62)

A solution of 2-thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-6, 103 mg,0.476 mmol), (2S)-2-Hydroxy-2-phenyl-propionic acid (79 mg, 0.48 mmol)and diisopropylethylamine (0.166 mL, 0.95 mmol) in N,N-dimethylformamide(5 mL) was reacted at the ambient temperature withbenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate(PyBop, 273 mg, 0.52 mmol). After 3 h stirring at the same temperature,the reaction mixture was concentrated under the reduced pressure and theresidue was partitioned between ethyl acetate (50 mL) and aqueous sodiumbicarbonate solution (40 mL). The organic layer was washed with brine,separated, dried (MgSO₄) and concentrated in vacuo. The resulting crudeproduct was triturated with ethyl acetate (3 mL), collected byfiltration, and dried under the reduced pressure to afford(2S)-2-Hydroxy-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]propanamideas a white solid (3-62); ¹H NMR (500 MHz, DMSO-d₆) δ 12.88 (s, 1H), 9.72(s, 1H), 9.31 (s, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 7.65 (d, 2H, J=8.5Hz), 7.52 (m, 1H), 7.36 (m, 3H), 7.26 (m, 1H), 6.45 (s, 1H), 1.72 (s,3H).

Compounds 3-1 through 3-85 in Table 3 below were prepared as shown inExamples 5 and 6 from commercially available carboxylic acids or acylchlorides. In some instances, racemic mixtures were resolved into theoptically pure enatiomers using a Chiral Pak AD HPLC column.

The 3-Arylbutanoic acid portion in compounds 3-66 thru 3-71 was preparedby a known synthetic route; Takaya, Y.; Senda, T.; Kurushima, H.;Ogasawara, M.; Hayashi, T. Tetrahedron Asymmetry 1999, 10, 4047.

The. 1-Phenylcyclopropane carboxylic acid portion in compounds 3-74 thru3-78 was prepared by a known synthetic route; 1) Levin, J. I.Tetrahedron Lett. 1993, 34, 6211; 2) Corey, E. J.; Chaykovsky, M. J. Am.Chem. Soc. 1965, 87, 1353.

The 2-Hydroxyacetic acid portion in compounds 3-79, 3-82 and 3-83 wasprepared by a known synthetic route; Ross, R.; Carpita, A.; Pazzi, P.;Mannina, L.; Valensin, D. Tetrahedron 1999, 55, 11343.

Selected spectra are as follow: 3-52, ¹H NMR (500 MHz, DMSO-d₆) δ 12.88(s, 1H), 10.15 (s, 1H), 9.31 (s, 1H), 8.42 (s, 1H), 7.98 (s, 1H), 7.53(d, 1H, J=8.8 Hz), 7.42 (m, 4 H), 7.23 (d, 1H, J=8.8 Hz), 3.88 (m, 1H),1.43 (d, 3H, J=6.4 Hz); 3-55, ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s, 1H),10.13 (s, 1H), 9.31 (s, 1H), 8.41 (s, 1H), 8.05 (s, 1H), 7.51 (d, 1H,J=8.4 Hz), 7.42 (m, 6H), 3.31 (m, 1H), 2.39 (m, 1H), 1.04 (m, 3H), 0.67(d, 3H, J=10.5 Hz); 3-65, ¹H NMR (500 MHz, DMSO-d₆) δ 12.88 (s, 1H),10.17 (s, 1H), 9.32 (d, 1H, J=2.0 Hz), 8.38 (s, 1H), 8.03 (s, 1H), 7.52(s, 1H), 7.45 (d, 2H, J=8.5 Hz), 7.40 (d, 2H, J=8.5 Hz), 7.23 (s, 1H),3.30 (m, 1H), 2.34 (m, 1H), 1.03 (d, 3H, J=6.0 Hz), 0.69 (d, 3H, J=7.0Hz); ¹H NMR 3-74 (500 MHz, DMSO-d₆) δ 12.88 (s, 1H), 9.32 (s, 1H), 9.07(s, 1H), 8.38 (d, 1H, J=2.0 Hz), 7.92 (s, 1H, J=1.0 Hz), 7.49 (d, 1H,J=9.0 Hz), 7.46-7.41 (m, 4H), 7.23 (dd, 1H, J=8.5, 1.5 Hz), 1.48 (m,2H), 1.12 (m, 2H).

TABLE 3 # Structure Nomenclature 3-1

3-Phenoxy-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)- propionamide; HRMS =349.1113 3-2

2-Phenoxy-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)- acetamide; HRMS =351.0905 3-3

trans-5-([1-(2-Phenyl-cyclopropyl)-methanoyl]-amino}-2-thiazol4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro- acetate; HRMS =361.1054 3-4

5-(4-Phenyl-butanoylamino)-2-thiazol-4-yl-3H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HRMS = 363.1224 3-5

6-(3-Phenyl-butanoylamino)-2-thiazol-4-yl-1H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HRMS = 363.1217 3-6

(1R,2R)-2-Phenyl-cyclopropanecarboxylic acid (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide; HRMS = 361.1048 3-7

(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid (2-thiazol-4-yl-3H-benzoimidazol-5-yl)-amide; HRMS = 361.1048 3-8

2-Methyl-3-phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide; HEMS =363.1204 3-9

5-(2-Phenyl-butanoylamino)-2-thiazol-4-yl-3H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HEMS = 363.1268 3-10

5-{[1-(1-Phenyl-cyclopropyl)-methanoyl]-amino 1-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro- acetate; HRMS =361.1115 3-11

5-(2,3-Diphenyl-propanoylamino)-2-thiazol-4-yl-3H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HRMS = 425.1428 3-12

5-(2,2-Diphenyl-ethanoylamino)-2-thiazol-4-yl-3H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HRMS = 411.1271 3-13

5-(3-Cyclohexyl-propanoylamino)-2-thiazol-4-yl-3H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HRMS = 355.1583 3-14

5-(2-Bicyclo[2.2.1]hept-2-yl-ethanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoroacetate; HRMS = 353.14293-15

6-(2-Methyl-2-phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 363.1281 3-16

6-(2-Phenyl-propanoylamino)-2-thiazol-4-yl-1H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HRMS = 349.1118 3-17

6-(2-Methoxy-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 365.1063 3-18

6-(2-Hydroxy-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-iuni; 2,2,2-trifluoro-acetate; HRMS = 351.0894 3-19

6-(2-Hydroxy-2-phenyl-propanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 365.1057 3-20

6-(2-Indan-2-yl-ethanoylamino)-2-thiazol-4-yl-1H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HRMS = 375.1278 3-21

6-[(1-Indan-1-yl-methanoyl)-amino]-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 361.1119 3-22

6-(2-Cyclopentyl-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 403.156 3-23

6-(2-Cyclohexyl-2-phenyl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 417.1752 3-24

6-[2-(3,4-Dichloro-phenyl)-ethanoylamino]-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 403.0192 3-25

6-{[1-(1-Phenyl-cyclopentyl)-methanoyl]-amino}-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro- acetate; HRMS =389.1464 3-26

6-(3,3-Diphenyl-propanoylamino)-2-thiazol-4-yl-1H- benzoimidazol-1-ium;2,2,2-trifluoro-acetate; HRMS = 425.1429 3-27

6-(2-Biphenyl-4-yl-ethanoylamino)-2-thiazol-4-yl-1H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 411.1224 3-28

(3R)-3-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5- yl)-butyramide; HRMS= 363.1211 3-29

(3R)-3-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5- yl)-betyramide; HRMS= 363.1211 3-30

(2R)-2-Phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5- yl)-butyramide; HRMS= 363.1210 3-31

6-[2-(3-Fluoro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 353.0864 3-32

2-(3-Chloro-phenyl)-N-(2-thiazol-4-yl-1H- benzoimidazol-5-yl)-acetamide;HRMS = 369.0576 3-33

6-[2-(3-Methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 365.1074 3-34

N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-(4-trifluoromethyl-phenyl)-acetamide; HRMS = 403.085 3-35

N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-p-tolyl- acetamide; HRMS =349.1132 3-36

6-[2-(4-Nitro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 380.0821 3-37

N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-(3-trifluoromethyl-phenyl)-acetamide; HRMS = 403.0858 3-38

6-[2-(3-Nitro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 380.0826 3-39

6-[2-(4-Fluoro-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 353.0879 3-40

6-[2-(Bis-trifluoromethyl-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro- acetate; HRMS =471.0703 3-41

2-(4-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide;HRMS = 369.058 3-42

2-(3,4-Difluoro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide; HRMS = 371.0781 3-43

6-[2-(4-Methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 365.1088 3-44

2-(3,5-Dimethyl-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide; HRMS = 363.1288 3-45

2-(3,5-Difluoro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide; HRMS = 371.0781 3-46

2-(4-Chloro-3-nitro-phenyl)-N-(2-thiazol-4-yl-1H-benzoiniidazol-5-yl)-acetamide; HRMS = 414.0435 3-47

6-[2-(4-Isopropyl-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 377.1444 3-48

6-[2-(3-Fluoro-4-methoxy-phenyl)-ethanoylamino]-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro- acetate; HRMS =383.0988 3-49

N-(2-Thiazol-4-yl-1H-benzoimidazol-5-yl)-2-(3,4,5-trifluoro-phenyl)-acetamide; HRMS = 389.0689 3-50

2-(4-Nitro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide; HRMS = 394.0976 3-51

6-[2-(4-Hydroxy-phenyl)-propanoylamino]-2-thiazol-4-yl-3H-benzoixnidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 365.10733-52

2-(4-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-propionamide; HRMS = 383.0739 3-53

6-(2-Benzo[1,3]dioxol-5-yl-ethanoylamino)-2-thiazol-4-yl-3H-benzoimidazol-1-ium; 2,2,2-trifluoro-acetate; HRMS = 379.08653-54

2-(4-Chloro-phenyl)-2-hydroxy-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide; HRMS = 385.0526 3-55

3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H- benzoimidazol-5-yl)-butyramide;HRMS = 377.1437 3-56

(2R)-2-(4-Chloro-phenyl)-2-hydroxy-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide; HRMS = 383.0739 3-57

(2S)-2-(4-Chloro-phenyl)-2-hydroxy-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-acetamide; HRMS = 383.0739 3-58

(2R)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide; HRMS = 377.1437 3-59

(2S)-3-Methyl-2-phenyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide; HRMS = 377.1437 3-60

3-(3-Chloro-phenyl)-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide; HRMS = 397.0878 3-61

(2R)-2-Hydroxy-2-phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide; HRMS = 365.0133 3-62

(2S)-2-Hydroxy-2-phenyl-N-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-propionamide; HRMS = 365.0133 3-63

2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide; HRMS = 411.93 3-64

(2R)-2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide; HRMS = 411.93 3-65

(2S)-2-(4-Chlorophenyl)-3-methyl-N-(2-thiazol-4-yl-1H-benzoimidazol-5-yl)-butyramide; HRMS = 411.9314 3-66

3-(3-(3-Chlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 396.8944 3-67

3-(4-Methylphenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 376.1343 3-68

3-(3-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 380.4380 3-69

3-(4-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 380.4380 3-70

3-(4-Chlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 396.8944 3-71

3-(2-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 380.4377 3-72

3-(4-Methylphenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 404.5279 3-73

2-(4-Fluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]propanamide; HRMS = 366.4122 3-74

1-(4-Chlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide; HRMS = 394.8770 3-75

1-(3-Fluorophenyl)-N-[2-(l,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide; HRMS = 378.4220 3-76

1-(3-Chlorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide; HRMS = 394.8769 3-77

1-(3,5-Dichlorophenyl)-N-[2-(1,3-thiazal-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide; HRMS = 429.3224 3-78

1-(3,5-Difluorophenyl)-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]cyclopropanecarboxamide; HRMS = 396.4132 3-79

2-Hydroxy-3-methyl-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 392.4748 3-80

(2R)-2-Hydroxy-3-methyl-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 392.4754 3-81

(28)-2-Hydroxy-3-methyl-2-phenyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 392.4754 3-82

2-Cyclopropyl-2-hydroxy-2-phenyl-N-(2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]acetamide; HRMS = 390.4580 3-83

2-(3-Chlorophenyl)-2-hydroxy-3-methyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 426.9194 3-84

(2R)-2-(3-Chlorophenyl)-2-hydroxy-3-methyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 426.9197 3-85

(2S)-2-(3-Chlorophenyl)-2-hydroxy-3-methyl-N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]butanamide; HRMS = 426.9204

Example 7

Pharmaceutical Composition

As a specific embodiment of this invention, 100 mg of6-({[(3-nitrophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-1H-benzimidazol-1-iumtrifluoroacetate, is formulated with suffiecient finely devided lactoseto provide a total amount of 580 to 590 mg to fill a size 0, hardgelatin capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, it isunderstood that the practice of the invention encompasses all of theusual variations, adoptions, or modifications, as being within the scopeof the following claims and their equivalents.

Assays

In vitro and in vivo Assays for Identification of Compounds with SarmActivity

The compounds exemplified in the present application exhibited activityin one or more of the following assays.

Hydroxylapatite-based Radioligand Displacement Assay of CompoundAffinity for Endogenously Expressed AR

Materials:

-   Binding Buffer: TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mM    beta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2)-   50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM    Tris, pH 8.0 and 1 mM EDTA.-   Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA.-   95% EtOH-   Methyltrienolone, [17α-methyl-³H], (R1881*); NEN NET590-   Methyltrienolone (R1881), NEN NLP005 (dissolve in 95% EtOH)-   Dihydrotestosterone (DHT) [1,2,4,5,6,7-³H(N)] NEN NET453-   Hydroxylapatite Fast Flow; Calbiochem Cat#391947-   Molybdate=Molybdic Acid (Sigma, M1651)    MDA-MB-453 cell culture media:

RPMI 1640 (Gibco 11835-055) w/23.8 mM NaHCO₃, 2 mM L-glutamine Finalconc. In 500 mL of complete media  10 mL(1M Hepes) 20 mM   5 mL (200 mML-glu)  4 mM 0.5 mL (10 mg/mL human insulin) 10 μg/mL in 0.01 N HClCalbiochem#407694-S)  50 mL FBS (Sigma F2442) 10%   1 mL (10 mg/mLGentamicin 20 μg/mL Gibco#15710-072)Cell Passaging:

Cells (Hall R. E., et al., European Journal of Cancer, 30A: 484-490(1994)) are rinsed twice in PBS, phenol red-free Trypsin-EDTA is dilutedin the same PBS 1:10. The cell layers are rinsed with 1× Trypsin, extraTrypsin is poured out, and the cell layers are incubated at 37° C. for˜2 min. The flask is tapped and checked for signs of cell detachment.Once the cells begin to slide off the flask, the complete media is addedto kill the trypsin. The cells are counted at this point, then dilutedto the appropriate concentration and split into flasks or dishes forfurther culturing (Usually 1:3 to 1:6 dilution).

Preparation of MDA-MB-453 Cell Lysate

When the MDA cells are 70 to 85% confluent, they are detached asdescribed above, and collected by centrifuging at 1000 g for 10 min at4° C. The cell pellet is washed twice with TEGM (10 mM Tris-HCl, 1 mMEDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate,pH 7.2). After the final wash, the cells are resuspended in TEGM at aconcentration of 10⁷ cells/mL. The cell suspension is snap frozen inliquid nitrogen or ethanol/dry ice bath and transferred to −80° C.freezer on dry ice. Before setting up the binding assay, the frozensamples are left on ice-water to just thaw (˜1 hr). Then the samples arecentrifuged at 12,500 g to 20,000 g for 30 min at 4° C. The supernatantis used to set-up assay right away. If using 50 μL of supernatant, thetest compound can be prepared in 50 μL of the TEGM buffer.

Procedure for Multiple Compound Screening:

1×TEGM buffer is prepared, and the isotopeontaining assay mixture isprepared in the following order: EtOH (2% final concentration inreaction), ³H-R1881 or ³H-DHT (0.5 nM final Conc. in reaction) and1×TEGM. [eg. For 100 samples, 200 μL (100×2) of EtOH+4.25 μL of 1:10³H-R1881 stock+2300 μL (100×23) 1×TEGM]. The compound is seriallydiluted, e.g., if starting final conc. is 1 μM, and the compound is in25 μL of solution, for duplicate samples, 75 μL of 4×1 μM solution ismade and 3 μL of 100 μM is added to 72 μL of buffer, and 1:5 serialdilution.

25 μL of ³H-R1881 trace and 25 μL compound solution are first mixedtogether, followed by addition of 50 μL receptor solution. The reactionis gently mixed, spun briefly at about 200 rpm and incubated at 4° C.overnight. 100 μL of 50% HAP slurry is prepared and added to theincubated reaction which is then vortexed and incubated on ice for 5 to10 minutes. The reaction mixture is vortexed twice more to resuspend HAPwhile incubating reaction. The samples in 96-well format are then washedin wash buffer using The FilterMate™ Universal Harvester plate washer(Packard). The washing process transfers HAP pellet containingligand-bound expressed receptor to Unifilter-96 GF/B filter plate(Packard). The HAP pellet on the filter plate is incubated with 50 μL ofMICROSCINT (Packard) scintillint for 30 minutes before being counted onthe TopCount microscintillation counter (Packard). IC_(50s) arecalculated using R1881 as a reference. Tissue selective androgenreceptor modulators of the present invention displayed IC₅₀ values of 1micromolar or less.

MMP1 Promoter Suppression, Transient Transfection Assay (TRAMPS)

HepG2 cells are cultured in phenol red free MEM containing 10%charcoal-treated FCS at 37C with 5% CO₂. For transfection, cells areplated at 10,000 cells/well in 96 well white, clear bottom plates.Twenty four hours later, cells are co-transfected with a MMP1promoter-luciferase reporter construct and a rhesus monkey expressionconstruct (50:1 ratio) using FuGENE6 transfection reagent, following theprotocol recommended by manufacturer. The MMP1 promoter-luciferasereporter construct is generated by insertion of a human MMP1 promoterfragment (−179/+63) into pGL2 luciferase reporter construct (Promega)and a rhesus monkey AR expression construct is generated in a CMV-Tag2Bexpression vector (Stratagene). Cells are further cultured for 24 hoursand then treated with test compounds in the presence of 100 nMphorbol-12-myristate-13-acetate (PMA), used to increase the basalactivity of MMP1 promoter. The compounds are added at this point, at arange of 1000 nM to 0.03 nM, 10 dilutions, at a concentration on 10×,1/10th volume (example: 10 microliters of ligand at 10× added to 100microliters of media already in the well). Cells are further culturedfor an additional 48 hours. Cells are then washed twice with PBS andlysed by adding 70 μL of Lysis Buffer (1×, Promega) to the wells. Theluciferase activity is measured in a 96-well format using a 1450Microbeta Jet (Perkin Elmer) luminometer. Activity of test compounds ispresented as suppression of luciferase signal from the PMA-stimulatedcontrol levels. EC₅₀ and Emax values are reported. Tissue selectiveandrogen receptor modulators of the present invention activaterepression typically with submicromolar EC₅₀ values and Emax valuesgreater than about 50%.

See Newberry E P, Willis D, Latifi T, Boudreaux J M, Towler D A,“Fibroblast growth factor receptor signaling activates the humaninterstitial collagenase promoter via the bipartite Ets-AP1 element,”Mol. Endocrinol. 11: 112944 (1997) and Schneikert J, Peterziel H,Defossez P A, Klocker H, Launoit Y, Cato A C, “Androgen receptor-Etsprotein interaction is a novel mechanism for steroid hormone-mediateddown-modulation of matrix metalloproteinase expression,” J. Biol. Chem.271: 23907-23913 (1996).

Mammalian Two-Hybrid Assay for the Ligand-Induced Interaction ofN-Terminus and C-Terminus Domains of the Androgen Receptor (AgonistMode)

This assay assesses the ability of AR agonists to induce the interactionbetween the N-terminal domain (NTD) and C-terminal domain (CTD) of rhARthat reflects the in vivo virilizing potential mediated by activatedandrogen receptors. The interaction of NTD and CTD of rhAR is quantifiedas ligand induced association between a Gal4DBD-rhARCTD fusion proteinand a VP16-rhARNTD fusion protein as a mammalian two-hybrid assay inCV-1 monkey kidney cells.

The day before transfection, CV-1 cells are trypsinized and counted, andthen plated at 20,000 cells/well in 96-well plates or larger plates(scaled up accordingly) in DMEM+10% FCS. The next morning, CV-1 cellsare cotransfected with pCBB1 (Gal4DBD-rhARLBD fusion construct expressedunder the SV40 early promoter), pCBB2 (VP16-rhAR NTD fusion constructexpressed under the SV40 early promoter) and pFR (Gal4 responsiveluciferase reporter, Promega) using LIPOFECTAMINE PLUS reagent(GIBCO-BRL) following the procedure recommended by the vendor. Briefly,DNA admixture of 0.05 μg pCBB1, 0.05 μg pCBB2 and 0.1 μg of pPR is mixedin 3.4 μL OPTI-MEM (GIBCO-BRL) mixed with “PLUS Reagent” (1.6 μL,GIBCO-BRL) and incubated at room temperature (RT) for 15 min to form thepre-complexed DNA.

For each well, 0.4 μL LIPOFECTAMINE Reagent (GIBCO-BRL) is diluted into4.6 μL OPTI-MBM in a second tube and mixed to form the dilutedLIPOFECTAMIE Reagent. The pre-complexed DNA (above) and the dilutedLIPOFECTAME Reagent (above) are combined, mixed and incubated for 15 minat RT. The medium on the cells is replaced with 40 μL/well OPTI-MEM, and10 μL DNA-lipid complexes are added to each well. The complexes aremixed into the medium gently and incubated at 37° C. at 5% CO₂ for 5 h.Following incubation, 200 μL /well D-MEM and 13% charcoal-stripped FCSare added, followed by incubation at 37° C. at 5% CO₂. After 24 hours,the test compounds are added at the desired concentration(s) (1 nM-10μM). Forty eight hours later, luciferase activity is measured usingLUC-Screen system (TROPIX) following the manufacturer's protocol. Theassay is conducted directly in the wells by sequential addition of 50 μLeach of assay solution 1 followed by assay solution 2. After incubationfor 40 minutes at room temperature, luminescence is directly measuredwith 2-5 second integration.

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with 3 nM R1881. Typical tissue-selective androgenreceptor modulators of the present invention display weak or no agonistactivity in this assay with less than 50% agonist activity at 10micromolar.

See He B, Kemppainen J A, Voegel J J, Gronemeyer H, Wilson E M,“Activation function in the human androgen receptor ligand bindingdomain mediates inter-domain communication with the NH(2)-terminaldomain,” J. Biol. Chem. 274: 37219-37225 (1999).

A Mammalian Two-Hybrid Assay For Inhibition of Interaction betweenN-Terminus and C-Terminus Domains of Androgen Receptor (Antagonist Mode)

This assay assesses the ability of test compounds to antagonize thestimulatory effects of R1881 on the interaction between NTD and CTD ofrhAR in a mammalian two-hybrid assay in CV-1 cells as described above.

Forty eight hours after transfection, CV-1 cells are treated with testcompounds, typically at 10 μM, 3.3 μM, 1 μm, 0.33 μM, 100 nM, 33 nM, 10nM, 3.3 nM and 1 nM final concentrations. After incubation at 37° C. at5% CO₂ for 10-30 minutes, an AR agonist methyltrienolone (R1881) isadded to a final concentration of 0.3 nM and incubated at 37° C.Forty-eight hours later, luciferase activity is measured usingLUC-Screen system (TROPIX) following the protocol recommended by themanufacturer. The ability of test compounds to antagonize the action ofR1881 is calculated as the relative luminescence compared to the valuewith 0.3 nM R1881 alone.

SARM compounds of the present invention typically displayed antagonistactivity in the present assay with IC₅₀ values less than 1 micromolar.

Trans-Activation Modulation of Androgen Receptor (TAMAR)

This assay assesses the ability of test compounds to controltranscription from the MMI-LUC reporter gene in MDA-MB453 cells, a humanbreast cancer cell line that naturally expresses the human AR. The assaymeasures induction of a modified MMTV LTR/promoter linked to the LUCreporter gene.

20,000 to 30,000 cells/well are plated in a white, clear-bottom 96-wellplate in “Exponential Growth Medium” which consists of phenol red-freeRPMI 1640 containing 10% FBS, 4 mM L-glutamine, 20 mM HEPES, 10 ug/mLhuman insulin, and 20 ug/mL gentamicin. Incubator conditions are 37° C.and 5% CO₂. The transfection is done in batch mode. The cells aretrypsinized and counted to the right cell number in the proper amount offresh media, and then gently mixed with the Fugene/DNA cocktail mix andplated onto the 96-well plate. All the wells receive 200 T1 ofmedium+lipid/DNA complex and are then incubated at 37° C. overnight.

The transfection cocktail consists of serum-free Optimem, Fugene6reagent and DNA. The manufacturer's (Roche Biochemical) protocol forcocktail setup is followed. The lipid (T1) to DNA Tg) ratio isapproximately 3:2 and the incubation time is 20 min at room temperature.Sixteen to 24 hrs after transfection, the cells are treated with testcompounds such that the final DMSO (vehicle) concentration is <3%. Thecells are exposed to the test compounds for 48 hrs. After 48 hrs, thecells are lysed by a Promega cell culture lysis buffer for 30-60 min andthen the luciferase activity in the extracts is assayed in the 96-wellformat luminometer.

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with 100 nM R1881.

See R. E. Hall, et al., “MDA-MB453, an androgen-responsive human breastcarcinoma cell line with high androgen receptor expression,” Eur. J.Cancer, 30A: 484-490 (1994) and R. E. Hall, et al., “Regulation ofandrogen receptor gene expression by steroids and retinoic acid in humanbreast-cancer cells,” Int. J. Cancer., 52: 778-784 (1992).

In Vivo Prostate Assay

Male Sprague-Dawley rats aged 9-10 weeks, the earliest age of sexualmaturity, are used in prevention mode. The goal is to measure the degreeto which androgen-like compounds delay the rapid deterioration (˜−85%)of the ventral prostate gland and seminal vesicles that occurs during aseven day period after removal of the testes (orchiectomy [ORX]).

Rats are orchiectomized (ORX). Each rat is weighed, then anesthetized byisoflurane gas that is maintained to effect. A 1.5 cm anteroposteriorincision is made in the scrotum. The right testicle is exteriorized. Thespermatic artery and vas deferens are ligated with 4.0 silk 0.5 cmproximal to the testicle. The testicle is freed by one cut of a smallsurgical scissors distal to the ligation site. The tissue stump isreturned to the scrotum. The same is repeated for the left testicle.When both stumps are returned to the scrotum, the scrotum and overlyingskin are sutured closed with 4.0 silk. For Sham-ORX, all proceduresexcepting ligation and scissors cutting are completed. The rats fullyrecover consciousness and full mobility within 10-15 minutes.

A dose of test compound is administered subcutaneously or orally to therat immediately after the surgical incision is sutured. Treatmentcontinues for an additional six consecutive days.

Necropsy and Endpoints:

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 ml whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofORX. Next, the ventral portion of the prostate gland is located andblunt dissected free in a highly stylized fashion. The ventral prostateis blotted dry for 3-5 seconds and then weighed (VPW). Finally, theseminal vesicle is located and dissected free. The ventral seminalvesicle is blotted dry for 3-5 seconds and then weighed (SVWT).

Primary data for this assay are the weights of the ventral prostate andseminal vesicle. Secondary data include serum LH (luteinizing hormone)and FSH (follicle stimulating hormone), and possible serum markers ofbone formation and virilization. Data are analyzed by ANOVA plus FisherPLSD post-hoc test to identify intergroup differences. The extent towhich test compounds inhibit ORX-induced loss of VPW and SVWT isassessed.

In Vivo Bone Formation Assay:

Female Sprague-Dawley rats aged 7-10 months are used in treatment modeto simulate adult human females. The rats have been ovariectomized (OVX)75-180 days previously, to cause bone loss and simulate estrogendeficient, osteopenic adult human females. Pre-treatment with a low doseof a powerful anti-resorptive, alendronate (0.0028 mpk SC, 2X/wk) isbegun on Day 0. On Day 15, treatment with test compound is started. Testcompound treatment occurs on Days 15-31 with necropsy on Day 32. Thegoal is to measure the extent to which androgen-like compounds increasethe amount of bone formation, shown by increased fluorochrome labeling,at the periosteal surface.

In a typical assay, nine groups of seven rats each are studied.

On Days 19 and 29 (fifth and fifteenth days of treatment), a singlesubcutaneous injection of calcein (8 mg/kg) is given to each rat.

Necropsy and Endpoints:

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 mL whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofOVX. First, the uterus is located, blunt dissected free in a highlystylized fashion, blotted dry for 3-5 seconds and then weighed (UW). Theuterus is placed in 10% neutral-buffered formalin. Next, the right legis disarticulated at the hip. The femur and tibia are separated at theknee, substantially defleshed, and then placed in 70% ethanol.

A 1-cm segment of the central right femur, with the femoralproximal-distal midpoint ats center, is placed in a scintillation vialand dehydrated and defatted in graded alcohols and acetone, thenintroduced to solutions with increasing concentrations of methylmethacrylate. It is embedded in a mixture of 90% methyl methacrylate:10%dibutyl phthalate, that is allowed to polymerize over a 48-72 hr period.The bottle is cracked and the plastic block is trimmed into a shape thatconveniently fits the vice-like specimen holder of a Leica 1600 SawMicrotome, with the long axis of the bone prepared for cross-sectioning.Three cross-sections of 85 μm thickness are prepared and mounted onglass slides. One section from each rat that approximates the midpointof the bone is selected and bihnd-coded. The periosteal surface of eachsection is assessed for total periosteal surface, single fluorochromelabel, double fluorochrome label, and interlabel distance.

Primary data for this assay are the percentage of periosteal surfacebearing double label and the mineral apposition rate (interlabeldistance(μm)/10 d), semi-independent markers of bone formation.Secondary data include uterus weight and histologic features. Tertiaryendpoints can include serum markers of bone formation and virilization.Data are analyzed by ANOVA plus Fisher PLSD post-hoc test to identifyintergroup differences. The extent to which test compounds increase boneformation endpoint are assessed.

1. A compound of formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:a is 0 or 1; b is 0 or 1; R¹ is thiazolyl, optionally substituted withone or more R⁴ groups; R² is —(C═O)NR⁵R⁶; R³ and R⁴ are eachindependently selected from: 1) hydrogen, 2) halogen, 3)—(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, 4) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl, 5)—(C═O)_(a)O_(b)(C₂₋₈)alkynyl, 6) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, 7)—(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl, 8) —(C═O)_(a)O_(b)aryl, 9)—(C═O)_(a)NR⁵R⁶, 10) —O_(b)(C═O)NR⁵R⁶, 11) —NR⁵(C═O)_(a)O_(b)R^(b), 12)—NR⁵(C═O)NR⁵R⁶, 13) —NR⁵S(O)₂R^(b), 14) —(C═O)OH, 15) trifluoromethoxy,16) trifluoroethoxy, 17) —O_(b)(C₁₋₁₀)perfluoroalkyl, 18)—S(O)₂O_(b)(C₁₋₁₀)alkyl, 19) —S(O)₂O_(b)(C₂₋₈)alkenyl, 20)—S(O)₂O_(b)(C₂₋₈)alkynyl, 21) —S(O)₂O_(b)(C₃₋₁₀)cycloalkyl, 22)—S(O)₂O_(b)(C₃₋₈)heterocyclyl, 23) —S(O)₂O_(b)aryl, 24) —NR⁵S(O)₂NR⁵R⁶,25) —CN 26) —NO₂, and 27) OH, wherein, said aryl, alkyl, alkenyl,alkynyl, heterocyclyl, and cycloalkyl are each optionally substitutedwith one or more R^(Z) groups; R⁵ is selected from: 1) hydrogen, 2)—(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, 3) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl, 4)—(C═O)_(a)O_(b)(C₂₋₈)alkynyl, 5) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, 6)—(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl, 7) —(C═O)_(a)O_(b)aryl, 8)—(C═O)N(R^(b))₂, 9) trifluoromethoxy, 10) trifluoroethoxy, 11)—(C₁₋₁₀)perfluoroalkyl, 12) —S(O)₂N(R^(b))₂, and 13) —S(O)₂O_(b)R^(b),wherein said alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynylare each optionally substituted with one or more R^(Z) groups, R⁶ isselected from: 1) —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, 2)—(C═O)_(a)O_(b)(C₂₋₈)alkenyl, 3) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl, 4)—(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, 5) —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,6) —(C═O)_(a)O_(b)aryl, 7) —(C═O)N(R^(b))₂, 8) trifluoromethoxy, 9)trifluoroethoxy, 10) —(C₁₋₁₀)perfluoroalkyl, 11) —S(O)₂N(R^(b))₂, and12) —S(O)₂O_(b)R^(b), wherein, said aryl, heterocyclyl, alkenyl, andalkynyl are optionally substituted with one or more R^(Z) groups, andwherein said alkyl and cycloalkyl are substituted with one or more R^(Z)groups, with the proviso that R^(Z) is other than hydrogen when R⁶ isalkyl or cycloalkyl, R^(Z) is selected from: 1) hydrogen, 2) halogen, 3)—(C═O)_(a)O_(b)(C₂₋₈)alkenyl, 4) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl, 5)—(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, 6) —(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl,7) —(C═O)_(a)O_(b)aryl, 8) —(C═O)_(a)N(R^(b))₂, 9) —O_(b)(C═O)N(R^(b))₂,10) —NR^(b)(C═O)_(a)O_(b)R^(b), 11) —NR^(b)(C═O)N(R^(b))₂, 12)—NR^(b)S(O)₂R^(b), 13) —(C═O)OH, 14) trifluoromethoxy, 15)trifluoroethoxy, 16) —O_(b)(C₁₋₁₀)perfluoroalkyl, 17)—S(O)₂O_(b)(C₁₋₁₀)alkyl, 18) —S(O)₂O_(b)(C₂₋₈)alkenyl, 19)—S(O)₂O_(b)(C₂₋₈)alkynyl, 20) —S(O)₂O_(b)(C₃₋₁₀)cycloalkyl, 21)—S(O)₂O_(b)(C₃₋₈)heterocyclyl, 22) —S(O)₂O_(b)aryl, 23) —S(O)₂N(R^(b))₂24) —NR^(b)S(O)₂N(R^(b))₂ 25) —CN, 26) —NO₂, 27) oxo, and 28) —OH,wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl are each optionally substituted with one or more R^(a)groups; R^(a) is selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen,CO₂H, CN, O(C═O)C₁₋₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,—O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and R^(b) is hydrogen,—(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, —(C═O)_(a)O_(b)(C₂₋₈)alkenyl,—(C═O)_(a)O_(b)(C₂₋₈)alkynyl, —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,—(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl, —(C═O)_(a)O_(b)aryl,—(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, —S(O)₂N(R^(a))₂, —S(O)₂O_(b)R^(a),trifluoromethoxy, trifluoroethoxy, or —O_(b)(C₁₋₁₀)perfluoroalkyl, andwherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclylare optionally substituted with up to three substituents selected fromCO₂H, NH₂, OH, (C₁₋₆)alkoxy, halogen, CN, O(C═O)C₁₋₆alkyl, NO₂,trifluoromethoxy, trifluoroethoxy, —O_(b)(C₁₋₁₀)perfluoroalkyl andN(R^(a))₂.
 2. A compound according to claim 1, wherein R¹ is selectedfrom thiazol-4-yl and thiazol-5-yl, wherein R¹ is optionally substitutedwith one or more R⁴ groups.
 3. A compound according to claim 2, wherein:R³ and R⁴ are each independently selected from: 1) hydrogen, 2) halogen,3) —(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, 4) —(C═O)_(a)O_(b)(C₂₋₈)alkenyl, 5)—(C═O)_(a)O_(b)(C₂₋₈)alkynyl, 6) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, 7)—(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl, 8) —(C═O)_(a)O_(b)aryl, 9)—(C═O)_(a)NR⁵R⁶, 10) —NR⁵S(O)₂R^(b), 11) trifluoroethoxy, 12)—O_(b)(C₁₋₁₀)perfluoroalkyl, 13) —S(O)₂O_(b)(C₁₋₁₀)alkyl, 14)—S(O)₂O_(b)(C₃₋₁₀)cycloalkyl, 15) —CN, and 16) OH, wherein said aryl,alkyl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl are eachoptionally substituted with one or more R^(Z) groups.
 4. A compoundaccording to claim 3, wherein: R⁵ is selected from: 1) hydrogen, 2)—(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, 3) —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl, 4)—(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl, 5) —(C═O)_(a)O_(b)aryl, 6) —(C═O)N(R^(b))₂, and 7) (C₁₋₁₀)perfluoroalkyl further wherein, said alkyl,cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl are optionallysubstituted with one or more R^(Z) groups, R⁶ is selected from: 1)—(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, 2) —(C═O)_(a)O_(b)(C_(3-l0))cycloalkyl, 3)—(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl, 4) —(C═O)_(a)O_(b)aryl, 5)—(C═O)N(R^(b))₂, and 6) (C₁₋₁₀)perfluoroalkyl further wherein said aryl,heterocyclyl, alkenyl, and alkynyl are optionally substituted with oneor more R^(Z) groups, and wherein said alkyl and cycloalkyl aresubstituted with one or more R^(Z) groups (providing R^(Z) is nothydrogen when R⁶ is alkyl or cycloalkyl).
 5. A compound according toclaim 4, wherein R^(b) is selected from: hydrogen,—(C═O)_(a)O_(b)(C₁₋₆)alkyl, —(C═O)_(a)O_(b)(C₃₋₆)cycloalkyl,—(C═O)_(a)O_(b)(C₃₋₆)heterocyclyl, —(C═O)_(a)O_(b)aryl, and(C₁₋₃)perfluoroalkyl, and wherein said alkyl, cycloalkyl, aryl, andheterocyclyl are optionally substituted with up to two substituentsselected from NH₂, OH, (C₁₋₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁₋₆alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,—O_(b)(C₁₋₁₀)perfluoroalkyl and N(R^(a))₂.
 6. A compound according toclaim 1, selected from:N-isopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-[(1R)-1-phenylpropyl]-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(3,5-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-benzyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(2-phenylethyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(2-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(2-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(2-chlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-[(1S)-1-phenylethyl]-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(3-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(4-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;N-(4-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;N-(2,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;N-(3,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-5-yl]urea;N-(4-methoxyphenyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(3-methylbenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-6-yl]urea;N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;N-(4-bromobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;N-(4-methoxybenzyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-6-yl]urea;6-({[(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-1H-benzimidazole;6-({[(1R)-1-phenylethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-[({[1-(1-naphthyl)ethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(3,5-difluorophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;N-methyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzinidazol-5-yl]urea;N-benzyl-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;N-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]-3,4-dihydroquinoline-1(2H)-carboxamide;N-ethyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;6-({[methyl(2-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[methyl(4-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;N-(4-hydroxyphenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(2-hydroxyethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(4-hydroxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;N-(2-chlorophenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(4-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(2-cyanoethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-[({methyl[4-(trifluoromethoxy)phenyl]-amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[benzyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[methyl(1-naphthyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[phenyl(1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[cyclohexyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;N-(1-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;N-(4-chlorophenyl)-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;6-({[(1-methyl-1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-[({[(1S)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(2,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;2-(1,3-thiazol-4-yl)-6[({[3(trifluoromethyl)benzyl]amino}carbonyl)amino]-3H-benzimidazole;6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-[({methyl[(1R)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-[({methyl[(1S)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-{[(2-phenylpyrrolidin-1-yl)carbonyl]amino}-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(2-phenylcyclopropyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-({[(4-methoxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-({[(5-isopropyl-2-methylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(6-methoxypyridinium-2-yl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(3,4-dichlorobenzyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-[({[(2-bromothien-3-yl)methyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-[({methyl[5-(trifluoromethyl)-1,3,4-thiadiazol-3-ium-2-yl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-({[(2,4-dichlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;N-cyclopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;N-[4-(hydroxymethyl)phenyl]-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea;1-[2-(3-Fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea;and pharmaceutically acceptable salts and stereoisomers thereof.
 7. Acompound according to claim 6, selected from:N-(3-fluorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-(3,4-dichlorobenzyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;N-benzyl-N-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;N-ethyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]urea;6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[isopropyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazole;6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazole;N-cyclopropyl-N-phenyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;and1-[2-(3-Fluoro-phenyl)-ethyl]-3-(2-thiazol-4-yl-3H-benzoimidazol-5-yl)-urea;and pharmaceutically acceptable salts and stereoisomers thereof.
 8. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1 and a pharmaceutically acceptable carrier.
 9. Acomposition of claim 8 which further comprises an active ingredientselected from: a) an estrogen or an estrogen derivative, alone or incombination with a progestin or progestin derivative; b) abisphosphonate; c) an antiestrogen or a selective estrogen receptormodulator, d) an αvβ3 integrin receptor antagonist, e) a cathepsin Kinhibitor, f) an HMG-CoA reductase inhibitor, g) an osteoclast vacuolarATPase inhibitor, h) an antagonist of VEGF binding to osteoclastreceptors, i) an activator of peroxisome proliferator-activated receptorγ, j) calcitonin, k) a calcium receptor antagonist, l) parathyroidhormone or analog thereof, m) a growth hormone secretagogue, n) humangrowth hormone, o) insulin-like growth factor, p) a p38 protein kinaseinhibitor, q) bone morphogenetic protein, r) an inhibitor of BMPantagonism, s) a prostaglandin derivative, t) vitamin D or vitamin Dderivative, u) vitamin K or vitamin K derivative, v) ipriflavone, w)fluoride salts, x) dietary calcium supplement, and y) osteoprotegerin.10. A composition of claim 9, wherein said bisphosphonate isalendronate.
 11. A pharmaceutical composition made by combining acompound according to claim 1 and a pharmaceutically acceptable carrier.12. A process for making a pharmaceutical composition comprisingcombining a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 13. A compound according to claim 1, selected from:6-({[(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-1H-benzimidazol-1-iumtrifluoroacetate;6-[({[(1R)-1-phenylethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({[(1-(1-naphthyl)ethyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3,5-difluorophenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[methyl(2-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[methyl(3-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[methyl(4-methylphenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(2-hydroxyethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(4-hydroxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzinidazol-1-iumtrifluoroacetate;6-({[(4-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(2-cyanoethyl)(phenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({methyl[4-(trifluoromethoxy)phenyl]-amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(benzyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[methyl(1-naphthyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-ium trifluoroacetate;6-({[phenyl(1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate6-({[cyclohexyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(1-methyl-1-phenylethyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({[(1S)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3-chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(2,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;2-(1,3-thiazol-4-yl-6[({[3(trifluoromethyl)benzyl]amino}carbonyl)amino]-3H-benzimidazol-1-iumtrifluoroacetate;6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({methyl[(1R)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({methyl[(1S)-1-phenylethyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-{[(2-phenylpyrrolidin-1-yl)carbonyl]amino}-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(2-phenylcyclopropyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(4-methoxyphenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(5-isopropyl-2-methylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(6-methoxypyridinium-2-yl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumbis(trifluoroacetate);6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3,4-dichlorobenzyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({[(2-bromothien-3-yl)methyl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({methyl[5-(trifluoromethyl)-1,3,4-thiadiazol-3-ium-2-yl]amino}carbonyl)amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumbis(trifluoroacetate); and6-({[(2,4-dichlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate; and stereoisomers thereof.
 14. A compound according toclaim 13, selected from:6-({[methyl(3-methylphenyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[isopropyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[sec-butyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[allyl(phenyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3-chlorophenyl)(methyl)amino]-carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-[({[(1R)-1-phenylpropyl]amino}carbonyl)-amino]-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-([{(3chlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3,5-dichlorobenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[benzyl(ethyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(3,5-dimethylphenyl)(methyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[ethyl(3-methylbenzyl)amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate; and stereoisomers thereof.
 15. A compound selectedfrom:N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl-1H-benzimidazol-6-yl]urea;6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;N-(1-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;andN-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea;16. A compound according to claim 15 which is:N-(1-phenylcyclopropyl)-N″-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea.17. A compound according to claim 15 selected from:N-(2-phenylcyclopropyl)-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-6-yl]urea;6-({[(3,4-dichlorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate;6-({[(2,4-difluorophenyl)(methyl)-amino]carbonyl}amino)-2-(1,3-thiazol-4-yl)-3H-benzimidazol-1-iumtrifluoroacetate; andN-methyl-N′-[2-(1,3-thiazol-4-yl)-1H-benzimidazol-5-yl]-N-[2-(trifluoromethoxy)-phenyl]urea.18. A compound according to claim 1 wherein R^(Z) is selected from: 1)—(C═O)_(a)O_(b)(C₂₋₈)alkenyl, 2) —(C═O)_(a)O_(b)(C₂₋₈)alkynyl, 3)—(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl, 4) —(C═O)_(a)O_(b)aryl, 5)—(C═O)_(a)N(R^(b))₂, 6) —O_(b)(C═O)N(R^(b))₂, 7)—NR^(b)(C═O)_(a)O_(b)R^(b), 8) —NR^(b)(C═O)N(R^(b))₂, 9)—NR^(b)S(O)₂R^(b), 10) —(C═O)OH, 11) trifluoromethoxy, 12)trifluoroethoxy, 13) —O_(b)(C₁₋₁₀)perfluoroalkyl, 14)—S(O)₂O_(b)(C₁₋₁₀)alkyl, 15) —S(O)₂O_(b)(C₂₋₈)alkenyl, 16)—S(O)₂O_(b)(C₂₋₈)alkynyl, 17) —S(O)₂O_(b)(C₃₋₁₀)cycloalkyl, 18)—S(O)₂O_(b)(C₃₋₈)heterocyclyl, 19) —S(O)₂O_(b)aryl, 20) —S(O)₂N(R^(b))₂21) —NR^(b)S(O)₂N(R^(b))₂ 22) —CN, 23) —NO₂, 24) oxo, and 25) —OH,wherein, said aryl, alkyl, alkenyl, alkynyl, heterocyclyl, andcycloalkyl are each optionally substituted with one or more R^(a)groups; R^(a) is selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen,CO₂H, CN, O(C═O)C₁₋₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,—O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and R^(b) is hydrogen,—(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, —(C═O)_(a)O_(b)(C₂₋₈)alkenyl,—(C═O)_(a)O_(b)(C₂₋₈)alkynyl, —(C═O)_(a)O_(b)(C₃₋₁₀)cycloalkyl,—(C═O)_(a)O_(b)(C₃₋₈)heterocyclyl, —(C═O)_(a)O_(b)aryl,—(C═O)_(a)O_(b)(C₁₋₁₀)alkyl, —S(O)₂N(R^(a))₂, —S(O)₂O_(b)R^(a),trifluormethoxy, trifluoroethoxy, or —O_(b)(C₁₋₁₀)perfluoroalkyl, andwherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclylare optionally substituted with up to three substituents selected fromCO₂H, NH₂, OH, (C₁₋₆)alkoxy, halogen, CN, O(C═O)C₁₋₆ alkyl, NO₂,trifluoromethoxy, trifluoroethoxy, —O_(b)(C₁₋₁₀)perfluoroalkyl andN(R^(a))₂.